The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Acute myeloid leukemia (AML) is a highly heterogenous and aggressive myeloid neoplasm. To sustain growth and survival, AML cells, like other neoplasms, require energy. This process is orchestrated by mitochondria and is under the control of several genes, such as PPRC1 (PRC), a member of the PGC-1 family, which is a key player in the transcription control of mitochondrial biogenesis. We have shown here that eugenol inhibits cell growth and promotes apoptosis through the mitochondrial pathway in AML cell lines as well as in cells from AML patients but not in cells from healthy donors. Similar effects were also observed on cytarabine-resistant AML cells. Interestingly, eugenol downregulated PPRC1 at both the protein and mRNA levels and reduced mitochondrial membrane potential in AML cells. We have also shown that PPRC1 expression is higher in cancer cells from blood, breast, and other types of cancer relative to normal cells, and high PPRC1 levels correlate significantly with short overall survival (OS). In addition, PPRC1 gene mutations significantly correlate with short OS and/or disease-free survival in several cancers. PPRC1 mutations also correlated significantly with poor OS (p < 0.0001) when tested in a total of 23,456 cancer patients. These findings suggest an oncogenic role of PPRC1 in various types of cancer and the possible eugenol-targeting of this gene for the treatment of AML patients, especially those exhibiting resistance to cytarabine.

Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection against diet-induced obesity. In this study, we used temporal metabolomics on HeLa cells to show that MTCH2 deletion results in a high ATP demand, an oxidized cellular environment, and elevated utilization of lipids, amino acids, and carbohydrates, accompanied by a decrease in several metabolites. Lipidomics analysis revealed a strategic adaptive reduction in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, MTCH2 knockout cells showed an increase in mitochondrial oxidative function, which may explain the higher energy demand. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion prevents NIH3T3L1 preadipocytes from differentiating into mature adipocytes, an energy consuming reductive biosynthetic process. In summary, the loss of MTCH2 leads to increased mitochondrial oxidative activity and energy demand, creating a catabolic and oxidative environment that fails to fuel the anabolic processes required for lipid accumulation and adipocyte differentiation.

Chemotherapeutic resistance is a major obstacle to the effectiveness of cisplatin-based chemotherapy for gastric cancer (GC), leading to treatment failure and poor survival rates. However, the underlying mechanisms are not fully understood. Our study demonstrated that the transcription factor myocyte enhancer factor 2A (MEF2A) plays a role in chemotherapeutic drug resistance by regulating the transcription of PGC1α and KEAP1, promoting mitochondrial biogenesis. It was found that increased MEF2A expression is linked with poor prognosis, cisplatin insensitivity, and mitochondrial function in GC. MEF2A overexpression significantly decreases GC cell sensitivity in vitro and in vivo, while MEF2A knockdown enhances the sensitivity to cisplatin. Mechanistically, MEF2A activates the transcription of PGC1α, leading to increased mitochondrial biogenesis. In addition, MEF2A inhibits KEAP1 transcription, reduces NRF2 ubiquitination degradation, and activates the KEAP1/NRF2 signaling pathway, which modulates the reactive oxygen species level. The present study identifies MEF2A as a new critical oncogene involved in GC chemoresistance, suggesting a novel therapeutic target for GC.

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI.

The involvement of microRNA-668 (miR-668) in the onset and progression of renal fibrosis remains unclear. To this end, we aimed to explore the relevant mechanism of miR-668 in renal fibrosis.

C57BL/6 J male mice were randomly divided into sham-operated, unilateral ureteral obstruction (UUO), and UUO-fenofibrate groups. Based on transfection and drug intervention, HK-2 cells were divided into blank control, TGF-β1, TGF-β1 + fenofibrate (PPARα agonist), mimics-NC, miR-668, mimics-NC + TGF-β1, miR-668 + TGF-β1, miR-668 + TGF-β1 + fenofibrate, miR-668 + TGF-β1 + GW6471 (PPARα inhibitor), mimics-NC + TGF-β1 + fenofibrate, and mimics-NC + TGF-β1 + GW6471 groups. The pathological changes in the renal tissues were observed by hematoxylin-eosin (HE) and Masson staining. The expression of PPARα, PGC-1α, miR-668, E-cadherin, Collagen III (Col III), and α-SMA in the renal tissues or HK-2 cells was detected by western blot, immunohistochemical analyses or real-time quantitative polymerase chain reaction. The regulatory effect of miR-668 on PPARα was verified by dual-luciferase reporter assay.

The expression of PPARα and PGC-1α decreased in UUO mice and TGF-β1-induced HK-2 cells, which was improved by fenofibrate. Compared to the non-transfected group, in TGF-β1-stimulated HK-2 cells, the expression of E-cadherin, PPARα and PGC-1α increased and the expression of Col III and α-SMA decreased in the miR-668-transfected group. The dual-luciferase reporter assay indicated the regulatory effect of hsa-mir-668-3p on PPARα.

MiR-668 can target PPARα and positively regulate the PPARα/PGC-1α pathway to alleviate renal fibrosis.

Ovarian aging is characterized by declines in follicular reserve and the emergence of mitochondrial dysfunction, reactive oxygen species production, inflammation, and fibrosis, which eventually results in menopause. Menopause is associated with increased systemic aging and the development of numerous comorbidities; therefore, the attenuation of ovarian aging could also delay systemic aging processes in women. Recent work has established that the anti-diabetic drug Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, elicits benefits on aging-related outcomes, likely through the modulation of nutrient-sensing pathways and metabolic homeostasis. Given that nutrient-sensing pathways play a critical role in controlling primordial follicle activation, we sought to determine if chronic Cana administration would delay ovarian aging and curtail the emergence of pathological hallmarks associated with reproductive senescence. We found that mice receiving Cana maintained their ovarian reserve through 12 months of age, which was associated with declines in primordial follicles FoxO3a phosphorylation, a marker of activation, when compared to the age-matched controls. Furthermore, Cana treatment led to decreased collagen, lipofuscin, and T cell accumulation at 12 months of age. Whole ovary transcriptomic and proteomic analyses revealed subtle improvements, predominantly in mitochondrial function and the regulation of cellular proliferation. Pathway analyses of the transcriptomic data revealed a downregulation in cell proliferation and mitochondrial dysfunction signatures, with an upregulation of oxidative phosphorylation. Pathway analyses of the proteomic data revealed declines in signatures associated with PI3K/AKT activity and lymphocyte accumulation. Collectively, we demonstrate that Cana treatment can delay ovarian aging in mice and could potentially have efficacy for delaying ovarian aging in women.

Genetic polymorphisms in nuclear respiratory factor-1 (Nrf1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β-cells. Expression of NRF1 target genes Tfam, Tfb1m and Tfb2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi-genomic gene transcription in diabetes.

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, a subsarcolemmal protein whose absence results in increased susceptibility of the muscle fiber membrane to contraction-induced injury. This results in increased calcium influx, oxidative stress, and mitochondrial dysfunction, leading to chronic inflammation, myofiber degeneration, and reduced muscle regenerative capacity. Fast glycolytic muscle fibers have been shown to be more vulnerable to mechanical stress than slow oxidative fibers in both DMD patients and DMD mouse models. Therefore, remodeling skeletal muscle toward a slower, more oxidative phenotype may represent a relevant therapeutic approach to protect dystrophic muscles from deterioration and improve the effectiveness of gene and cell-based therapies. The resistance of slow, oxidative myofibers to DMD pathology is attributed, in part, to their higher expression of Utrophin; there are, however, other characteristics of slow, oxidative fibers that might contribute to their enhanced resistance to injury, including reduced contractile speed, resistance to fatigue, increased capillary density, higher mitochondrial activity, decreased cellular energy requirements. This review focuses on signaling pathways and regulatory factors whose genetic or pharmacologic modulation has been shown to ameliorate the dystrophic pathology in preclinical models of DMD while promoting skeletal muscle fiber transition towards a slower more oxidative phenotype.

Cellular senescence is a condition characterized by stable, irreversible cell cycle arrest linked to the aging process. The accumulation of senescent cells in the cardiac muscle can contribute to various cardiovascular diseases (CVD). Telomere shortening, epigenetic modifications, DNA damage, mitochondrial dysfunction, and oxidative stress are known contributors to the onset of cellular senescence in the heart. The link between mitochondrial processes and cellular senescence contributed to the age-related decline in cardiac function. These include changes in mitochondrial functions and behaviours that arise from various factors, including impaired dynamics, dysregulated biogenesis, mitophagy, mitochondrial DNA (mtDNA), reduced respiratory capacity, and mitochondrial structural changes. Thus, regulation of mitochondrial biology has a role in cellular senescence and cardiac function in aging hearts. Targeting senescent cells may provide a novel therapeutic approach for treating and preventing CVD associated with aging. CYP epoxygenases metabolize N-3 and N-6 polyunsaturated fatty acids (PUFA) into epoxylipids that are readily hydrolyzed to diol products by soluble epoxide hydrolase (sEH). Increasing epoxylipids levels or inhibition of sEH has demonstrated protective effects in the aging heart. Evidence suggests they may play a role in cellular senescence by regulating mitochondria, thus reducing adverse effects of aging in the heart. In this review, we discuss how mitochondria induce cellular senescence and how epoxylipids affect the senescence process in the aged heart.

Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson's Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features.

To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation. We characterized adaptive, AD-associated gene, and AD-associated protein responses.

SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology.

Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena.

In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.

Metabolic syndrome is increasing worldwide, particularly in rural communities, where residents have a higher risk of exposure to pesticides. We investigated whether six commonly used agricultural pesticides on corn and soy fields possess adipogenic and metabolic disruption activity. Exposure to two of these pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure induced morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 µM and LC50 of 12 µM. Acetochlor exposure at 10 nM resulted in lipid accumulation in zebrafish larvae when simultaneously fed a high-cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we performed transcriptomic and lipidomic analyses of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consistent with this prediction, Gpx activity was efficiently repressed by acetochlor in zebrafish, whereas lipid peroxidation was increased. We propose that acetochlor disrupts lipid homeostasis by inhibiting GPX activity, resulting in the accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contains the chloroacetamide group, inhibition of GPX activity may represent a novel, common molecular initiating event of metabolic disruption.

Lipid droplets (LDs) are dynamic organelles that communicate with other cellular components to orchestrate energetic homeostasis and signal transduction. In skeletal muscle, the presence and importance of LDs have been widely studied in myofibers of both rodents and humans under physiological conditions and in metabolic disorders. However, the role of LDs in myogenic stem cells has only recently begun to be unveiled. In this review we briefly summarize the process of LD biogenesis and degradation in the most prevalent model. We then review recent knowledge on LDs in skeletal muscle and muscle stem cells. We further introduce advanced methodologies for LD imaging and mass spectrometry that have propelled our understanding of the dynamics and heterogeneity of LDs.

Neobavaisoflavone (NBIF) is a natural antioxidant that has a variety of pharmacological activities. To investigate the effects of NBIF on oxidative stress-induced myocardial injury, H9c2 cells were treated with H2O2. Cell counting kit-8 was used to detect cell viability. Intracellular as well as lipid radicals were detected. To measure mitochondrial function, tetramethylrhodamine ethyl ester was used to detect mitochondrial membrane potential. 12- and 15-hydroxyeicosatetraenoic acids (HETE) were measured by LC-MS/MS. ALOX15, which is the upstream protein of 12-, 15-HETE, was also measured by using western blot analysis. The results showed that H2O2 induced lipid peroxidation in cardiomyocytes and caused mitochondrial dysfunction which was relieved by NBIF treatment. Besides, H2O2 significantly increased the production of 12-HETE and 15-HETE and upregulated the expression of ALOX15 while PGC-1α was downregulated and triggered the release of cytochrome c. The treatment of NBIF decreased the expression of ALOX15 and inhibited the activation of caspase-3. NBIF protected mitochondrial membrane integrity through increasing PGC-1α and Nrf1. Our results indicated that NBIF could protect cardiomyocytes against H2O2-induced mitochondrial dysfunction via ALOX15/PGC-1α axis.

Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.

We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.

Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.

This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

To investigate the application of H2 to alleviate cardiac ischaemia-reperfusion (I/R) injury in a PGC-1α-dependent manner. A rat in vitro myocardial I/R injury model was used, Western blot was used to detect the expression levels of apoptosis markers (Bax, cleaved caspase-3, Bcl2), inflammatory factors (IL-1β, TNF-α), mitochondrial fission (DRP1, MFF) and mitochondrial fusion (MFN1, MFN2, OPA1). HE staining was used to observe the effect of H2 on the myocardial tissue structure injured by I/R. Transmission electron microscopy (TEM) was used to observe the changes in the mitochondrial structure of myocardial tissue after I/R injury. Real-time quantitative PCR (qPCR) was used to detect the expression of PGC-1α in the myocardial tissue of rats after I/R injury and H2 treatment. H2 increases the expression level of PGC-1α, while the deletion of PGC-1α inhibited the therapeutic effect of H2. H2 can improve the changes of the myocardial tissue and mitochondrial structure caused by I/R injury. H2 treatment effectively inhibited the inflammatory response, and the loss of PGC-1α could inhibit the therapeutic effect of H2. The application of H2 can alleviate myocardial I/R injury, and the loss of PGC-1α weakens the protective effect of H2 on the I/R heart.

For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.

Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.

The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.

There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.

Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice.

Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues.

In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice.

Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2's novel role as a regulator of obesity in female mice.

The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.

Lithium therapy received approval during the 1970s, and it has been used for its antidepressant, antimanic, and anti-suicidal effects for acute and long-term prophylaxis and treatment of bipolar disorder (BPD). These properties have been well established; however, the molecular and cellular mechanisms remain controversial. In the past few years, many studies demonstrated that at the cellular level, lithium acts as a regulator of neurogenesis, aging, and Ca2+ homeostasis. At the molecular level, lithium modulates aging by inhibiting glycogen synthase kinase-3β (GSK-3β), and the phosphatidylinositol (PI) cycle; latter, lithium specifically inhibits inositol production, acting as a non-competitive inhibitor of inositol monophosphatase (IMPase). Mitochondria and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) have been related to lithium activity, and its regulation is mediated by GSK-3β degradation and inhibition. Lithium also impacts Ca2+ homeostasis in the mitochondria modulating the function of the lithium-permeable mitochondrial Na+-Ca2+exchanger (NCLX), affecting Ca2+ efflux from the mitochondrial matrix to the endoplasmic reticulum (ER). A close relationship between the protease Omi, GSK-3β, and PGC-1α has also been established. The purpose of this review is to summarize some of the intracellular mechanisms related to lithium activity and how, through them, neuronal aging could be controlled.

Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury.

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.

The hypothalamus plays a central role in regulating energy expenditure and maintaining energy homeostasis, crucial for an organism's survival. Located in the ventral diencephalon, it is a dynamic and adaptable brain region capable of rapid responses to environmental changes, exhibiting high anatomical and cellular plasticity and integrates a myriad of sensory information, internal physiological cues, and humoral factors to accurately interpret the nutritional state and adjust food intake, thermogenesis, and energy homeostasis. Key hypothalamic nuclei contain distinct neuron populations that respond to hormonal, nutrient, and neural inputs and communicate extensively with peripheral organs like the gastrointestinal tract, liver, pancreas, and adipose tissues to regulate energy production, storage, mobilization, and utilization. The hypothalamus has evolved to enhance energy storage for survival in famine and scarce environments but contribute to obesity in modern contexts of caloric abundance. It acts as a master regulator of whole-body energy homeostasis, rapidly adapting to ensure energy supplies for cellular functions. Understanding hypothalamic function, pertaining to energy expenditure, is crucial for developing targeted interventions to address metabolic disorders, offering new insights into the neural control of metabolic states and potential therapeutic strategies.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.

Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

Mitochondrial dysfunction represents a pivotal aspect of the pathogenesis and progression of diabetic kidney disease (DKD). Central to the orchestration of mitochondrial biogenesis is the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α), a master regulator with a profound impact on mitochondrial function. In the context of DKD, PGC1-α exhibits significant downregulation within intrinsic renal cells, precipitating a cascade of deleterious events. This includes a reduction in mitochondrial biogenesis, heightened levels of mitochondrial oxidative stress, perturbed mitochondrial dynamics, and dysregulated mitophagy. Concurrently, structural and functional abnormalities within the mitochondrial network ensue. In stark contrast, the sustained expression of PGC1-α emerges as a beacon of hope in maintaining mitochondrial homeostasis within intrinsic renal cells, ultimately demonstrating an impressive renoprotective potential in animal models afflicted with DKD. This comprehensive review aims to delve into the recent advancements in our understanding of the renoprotective properties wielded by PGC1-α. Specifically, it elucidates the potential molecular mechanisms underlying PGC1-α's protective effects within renal tubular epithelial cells, podocytes, glomerular endothelial cells, and mesangial cells in the context of DKD. By shedding light on these intricate mechanisms, we aspire to provide valuable insights that may pave the way for innovative therapeutic interventions in the management of DKD.

Perfluorooctanoic acid (PFOA) is a synthetic organofluoride surfactant associated with several toxic effects in humans and animals. Particularly, it has been observed that PFOA treatment of mice results in weight loss associated with recruited brown adipose tissue (BAT), including an increased amount of uncoupling protein 1 (UCP1). The molecular mechanism behind this BAT recruitment is presently unknown. To investigate the existence of possible cell-autonomous effects of PFOA, we treated primary cultures of brown and white (inguinal) adipocytes with PFOA, or with the non-fluorinated equivalent octanoate, or with vehicle, for 48 h (from day 5 to day 7 of differentiation). PFOA in itself increased the gene expression (mRNA levels) of UCP1 and carnitine palmitoyltransferase 1A (CPT1α) (thermogenesis-related genes) in both brown and white adipocytes. In addition, PFOA increased the expression of fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor α (PPARα) (adipogenesis-related genes). Also the protein levels of UCP1 were increased in brown adipocytes exposed to PFOA. This increase was more due to an increase in the fraction of cells that expressed UCP1 than to an increase in UCP1 levels per cell. The PFOA-induced changes were even more pronounced under simultaneous adrenergic stimulation. Octanoate induced less pronounced effects on adipocytes than did PFOA. Thus, PFOA in itself increased the levels of thermogenic markers in brown and white adipocytes. This could enhance the energy metabolism of animals (and humans) exposed to the compound, resulting in a negative energy balance, leading to diminished fitness.

Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impaired the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice displayed increased fasting blood glucose levels and hepatic steatosis while on a chow diet. Foxj3 deficiency inhibited the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduced the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhanced the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and iWAT increased energy expenditure and improved systemic metabolism on either a chow or high-fat diet. Finally, Foxj3 deletion in fat inhibited the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulated the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. This study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.

Naringin, a natural flavanone primarily found in citrus fruits, has garnered increased attention due to its recognized antioxidative, anti-inflammatory, and cardioprotective attributes. However, the functions of naringin in regulating energy expenditure are poorly understood. In the present study, we observed that twelve weeks of naringin supplementation substantially reshaped the metabolic profile of high-fat diet (HFD)-fed mice, by inhibiting body weight gain, reducing liver weight, and altering body compositions. Notably, naringin exhibited a remarkable capacity to augment whole-body energy expenditure of the tested mice by enhancing the thermogenic activity of brown adipose tissue (BAT) and stimulating browning of inguinal white adipose tissue (iWAT). Furthermore, our results showed naringin supplementation modified gut microbiota composition, specifically increasing the abundance of Bifidobacterium and Lachnospiraceae_bacterium_28-4, while reducing the abundance of Lachnospiraceae_bacterium_DW59 and Dubosiella_newyorkensis. Subsequently, we also found naringin supplementation altered fecal metabolite profile, by significantly promoting the production of taurine, tyrosol, and thymol, which act as potent activators of thermoregulation. Interestingly, the metabolic effects of naringin were abolished upon gut microbiota depletion through antibiotic intervention, concurrently leading the disappearance of naringin-induced thermogenesis and protective actions on diet-induced obesity. This discovery revealed a novel food-driven cross-sectional communication between gut bacteria and adipose tissues. Collectively, our data indicate that naringin supplementation stimulates BAT thermogenesis, alters fat distribution, promotes the browning process, and consequently inhibits body weight gain; importantly these metabolic effects require the participation of gut bacteria.