Mitochondrial Biogenesis Research Articles

SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function.

SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function.

Mitochondria: An overview of their origin, genome, architecture, and dynamics.

Mitochondria: An overview of their origin, genome, architecture, and dynamics.

The Role of Exercise in Mitochondrial Remodeling as a Combatant to Muscular Dystrophy: A Literature Review

Introduction: Muscular dystrophy (MD) refers to a group of diseases characterized by the progressive degeneration and weakness of skeletal muscle. Mitochondrial dysfunction plays a central role in the pathology of many MD subtypes that arise from various genetic mutations. Elevated oxidative stress induced by MD is a key mechanism driving mitochondrial dysfunction in these conditions. This review explores the role of exercise-induced mitochondrial remodeling and its potential therapeutic implications in MD management. Methods: This literature review covers a comprehensive scope of studies published between 2018 to 2024 that were found using PubMed and OVID MEDLINE databases. The studies selected for this review focus on the effects of exercise on mitochondrial biogenesis and function in the context of muscular dystrophy. Results: Exercise and exercise mimetics were found to induce mitochondrial remodeling, improve oxidative metabolism, and reduce cellular oxidative stress in various preclinical MD models and MD patients. Aerobic and resistance training elicited increased mitochondrial mass, protein levels associated with oxidative phosphorylation (OXPHOS), and oxidative muscle fiber composition across different MD subtypes. However, variability in response was observed, suggesting exercise may not be beneficial for all MD patients. Discussion: Exercise is a potential therapeutic intervention in addressing mitochondrial dysfunction in MD patients. Moderate-intensity aerobic exercise demonstrates benefits in enhancing mitochondrial respiratory complexes thus suggesting it has a key role in improving mitochondrial function. MD models showed increased mitochondrial mass and respiratory complex protein levels in response to resistance exercise which is correlated with improved strength. In combination with pharmaceutical or gene therapies, exercise shows promise in mitigating MD pathology. Conclusion: Exercise-induced mitochondrial remodeling appears to induce several positive mitochondrial adaptations that play a role in mitigating MD pathology across various subtypes. Exercise prescription should be tailored to specific MD subtypes to optimize mitochondrial responses, and treatment should be focused on preserving muscle function in patients. Further research is required to support the use of a combination of exercise and pharmaceutical therapies as potential intervention for MD patients.

Oxidative phosphorylation and breast cancer progression: insights into PGC-1α's role in mitochondrial function.

Breast cancer still ranks high as a leading cause of mortality in women due to its complex relationship with metabolic reprogramming and tumor progression. The peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a key transcriptional coactivator regulating mitochondrial biogenesis and oxidative phosphorylation (OXPHOS), plays a dual role in breast cancer metabolism. On the one hand, PGC-1α enhances mitochondrial function and energy production, facilitating tumor survival and metastasis, particularly in hypoxic environments. On the other hand, its suppression can limit tumor aggressiveness and energy metabolism. This dual functionality underscores its context-dependent role in cancer progression, where its activation or inhibition varies across tumor subtypes and microenvironmental conditions. The purpose of this review is to provide a comprehensive understanding of PGC-1α's dual roles in breast cancer, elucidating its regulation of mitochondrial function, its contribution to tumor progression, and the therapeutic implications of targeting this key metabolic regulator.

The role of mitochondrial dysfunction in the protective effect of ginger derived extracellular vesicles on hepatic stellate cells against cytotoxicity.

Previous studies have shown that ginger-derived extracellular vesicles (Gin-EVs) can alleviate alcohol-induced liver injury. It remained unknown and needs to be further verified that whether the vesicles has therapeutic potential to alleviate the progression of liver fibrosis. Moreover, the relevant mechanisms need to be further studied. Herein, we provide evidence that Gin-EVs effectively interact with human hepatic stellate cells (LX-2), offering protection against carbon tetrachloride (CCL4) or lipopolysaccharides (LPS)-induced liver fibrosis. The treatment with Gin-EVs was observed to mitigate fibrosis and enhance cell viability in LX-2 cells exposed to CCL4 or LPS. Mechanistically, Gin-EVs counteracted mitochondrial dysfunction by restoring mitochondrial dynamics imbalance characterized by enhanced fusion and reduced fission events while promoting mitochondrial biogenesis, thereby potentially preventing fibrotic processes in LX-2 cells. Collectively, the findings highlight the direct cytoprotective effects of Gin-EVs on LX-2 cells and suggest their promising role as a therapeutic option for hepatic fibrosis.

Poncirus trifoliata Extract and Its Active Coumarins Alleviate Dexamethasone-Induced Skeletal Muscle Atrophy by Regulating Protein Synthesis, Mitochondrial Biogenesis, and Gut Microbiota.

Sarcopenia, an age-related decline in skeletal muscle mass and function, contributes to frailty and increased morbidity in the elderly. This necessitates the development of effective interventions to combat muscle atrophy. This study investigated the therapeutic potential of Poncirus trifoliata ethanol extract (PT) and its coumarin derivatives against dexamethasone (DEX)-induced muscle atrophy. We employed invitro and invivo models of DEX-induced muscle atrophy. C2C12 myotubes were used for mechanistic studies. C57BL/6J mice received DEX injections and oral PT supplementation (50 mg/kg/day) to evaluate effects on muscle mass, function, gene expression, and gut microbiota composition. Invitro, PT enhanced protein synthesis, mitochondrial biogenesis, and myogenic differentiation in DEX-exposed myotubes, with auraptene, ponciol, and triphasiol identified as key bioactive coumarins. Invivo, PT significantly attenuated DEX-induced muscle atrophy, increasing tibialis anterior muscle mass by 36% (p < 0.01), grip strength by 31% (p < 0.001), and maximal running speed by 18% (p < 0.05). Mechanistically, PT upregulated genes associated with muscle function and mitochondrial health. Furthermore, PT modulated gut microbiota composition, notably increasing Phocaeicola vulgatus abundance 2.2-fold, which correlated with improved muscle performance (R = 0.58, p < 0.01). These findings suggest that PT and its coumarin derivatives, particularly auraptene, ponciol, and triphasiol, hold promise as therapeutic agents for combating muscle atrophy. The observed benefits may be mediated through enhanced protein synthesis, improved mitochondrial function, and modulation of the gut-muscle axis.

Insulin resistance-induced mitochondrial dysfunction and pyroptosis in trophoblasts: protective role of metformin

BackgroundGestational diabetes mellitus (GDM) affects up to 14% of pregnancies globally, with insulin resistance (IR) playing a critical but often underappreciated role in its pathogenesis. Yet the specific impact of insulin at IR levels on mitochondrial function and pyroptosis in first-trimester trophoblasts remains unclear. Metformin use in GDM pregnancies is rising, but its impact on placental mitochondrial function is uncertain. This study aimed to investigate the impact of IR, a key feature of GDM, on mitochondrial dysfunction and pyroptosis in trophoblasts and to evaluate the protective effects of metformin.MethodsDual staining assays using TUNEL and caspase-1, and enzyme-linked immunosorbent assay were conducted to assess pyroptosis and pyroptosis-related inflammatory markers in placentas from 42 GDM patients and 39 controls. In vitro, HTR-8/SVneo trophoblast cells were treated with IR-level insulin concentrations, and a concentration gradient of metformin to evaluate the mitochondrial damage, pyroptosis, and cell viability.ResultsThere was a significant increase in pyroptosis in GDM placenta, as well as pyroptosis-related inflammatory markers, IL-1β and IL-18. Placental IL-1β and IL-18 levels were strongly correlated with IR indices, especially in GDM cases. Moreover, IR-level insulin concentrations induced mitochondrial dysfunction and activated the NLRP3 inflammasome, triggering pyroptosis in HTR-8/SVneo trophoblasts. Metformin, particularly at therapeutic doses (10–100 µM), mitigated IR-induced mitochondrial damage by promoting mitochondrial biogenesis and reducing pyroptosis via suppressing the ROS/TXNIP/NLRP3 pathway. Metformin-treated cells exhibited enhanced mitochondrial respiration, restored membrane potential homeostasis, and reduced oxidative stress.ConclusionIR, independent of hyperglycemia, drives placental inflammation and trophoblastic injury via pyroptosis. Targeting the ROS/TXNIP/NLRP3 pathway with metformin or other therapeutic agents offers potential therapeutic value in managing IR-related complications in GDM.

Lasmiditan Induces Mitochondrial Biogenesis in Primary Mouse Renal Peritubular Endothelial Cells and Augments Wound Healing and Tubular Network Formation.

Kidney disease (KD) is a progressive and life-threatening illness that has manifested into a global health crisis, impacting >10% of the general population. Hallmarks of KD include tubular interstitial fibrosis, renal tubular cell atrophy/necrosis, glomerulosclerosis, persistent inflammation, microvascular endothelial cell (MV-EC) dysfunction/rarefaction, and mitochondrial dysfunction. Following acute kidney injury (AKI), and/or during KD onset/progression, MV-ECs of the renal peritubular endothelial capillaries (RPECs) are highly susceptible to injury, dysfunction, and rarefaction. Pharmacological induction of mitochondrial biogenesis (MB) via 5-Hydroxytryptamine Receptor 1F (HTR1F) agonism has been shown to enhance mitochondrial function and renal vascular recovery post-AKI in mice; however, little is known about MB in relation to renal MV-ECs and RPECs repair mechanisms. To address this gap in knowledge, the in vitro effects of the potent and selective FDA-approved HTR1F agonist lasmiditan were tested on primary mouse renal peritubular endothelial cells (MRPECs). Lasmiditan increased mitochondrial maximal respiration rates, mRNA and protein expression of MB-related genes, and mitochondrial number in MRPECs. MRPECs were then exposed to pro-inflammatory agents associated with renal MV-EC dysfunction, AKI, and KD (i.e., lipopolysaccharides, transforming growth factor-β1, and tumor necrosis factor-α), in the presence/absence of lasmiditan. Lasmiditan treatment augmented MRPECs wound healing, endothelial tubular network formation (ETNF), enhanced barrier integrity, and blunted inflammatory-induced MV-EC dysfunctions. Together, these data suggest that lasmiditan induces MB and improves wound healing and ETNF of primary MRPECs in the presence/absence of pro-inflammatory agents, highlighting a potential therapeutic role for lasmiditan treatment in renal MV-EC dysfunction, AKI, and/or KD.

Heme metabolism mediates RANKL-induced osteoclastogenesis via mitochondrial oxidative phosphorylation.

Bone undergoes life-long remodelling, in which disorders of bone remodelling could occur in many pathological conditions including osteoporosis. Understanding the cellular metabolism of osteoclasts is key to developing new treatments for osteoporosis, a disease that affects over 200 million women worldwide per annum. We found that human osteoclast differentiation from peripheral blood mononuclear cells (PBMCs) derived from 8 female patients is featured with a distinct gene expression profile of mitochondrial biogenesis. Elevated mitochondrial membrane potential (MMP, Δψm) was also observed in RANKL-induced osteoclasts. Interestingly, the gene pathways of heme synthesis and metabolism were activated upon RANKL stimulation, featured by a transcriptomic profiling in murine cells at a single-cell resolution, which revealed a stepwise expression pattern of heme-related genes. The real-world human data also divulges potential links between heme-related genes and bone mineral density. Heme is known to have a role in the formation of functional mitochondrial complexes that regulate MMP. Disruption of heme biosynthesis via genetically silencing Ferrochelatase or a selective inhibitor, N-methyl Protoporphyrin IX (NMPP), demonstrated potent inhibition of osteoclast differentiation, with a dose-dependent effect observed in NMPP treatment and a substantial efficacy even at a single dose. In vivo study further showed the protective effect of NMPP on ovariectomy-induced bone loss in female mice. Collectively, we found that RANKL-mediated signaling regulated mitochondrial formation and heme metabolism to synergistically support osteoclastogenesis. Inhibition of heme synthesis impaired osteoclast formation and reversed excessive bone loss, representing a new therapeutic target for metabolic skeletal disorders.

The Nuclear-Mitochondrial Crosstalk in Aging: From Mechanisms to Therapeutics.

The Nuclear-Mitochondrial Crosstalk in Aging: From Mechanisms to Therapeutics.

An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress.

Cardiac β3-adrenergic receptors (ARs) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect against myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. However, the underlying mechanisms remain elusive. To dissect functional, transcriptional, and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human ADRB3 transgene (β3AR-Tg) and subjected to transverse aortic constriction were assessed with echocardiography, RNA sequencing, positron emission tomography scan, metabolomics, and metabolic flux analysis. Subsequently, signaling and metabolic pathways were further investigated in vivo in β3AR-Tg and ex vivo in neonatal rat ventricular myocytes adenovirally infected to express β3AR and subjected to neurohormonal stress. These results were complemented with an analysis of single-nucleus RNA-sequencing data from human cardiac myocytes from patients with heart failure. Compared with wild-type littermates, β3AR-Tg mice were protected from hypertrophy after transaortic constriction, and systolic function was preserved. β3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in the absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the pentose-phosphate pathway in β3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the pentose-phosphate pathway, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, whereas downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in β3AR-Tg mice after transaortic constriction compared with wild type, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as an upstream transcription factor that was functionally verified in vivo and in β3AR-expressing cardiac myocytes, where its translocation and nuclear activity were dependent on β3AR activation of nitric oxide synthase and nitric oxide production through S-nitrosation of the NRF2-negative regulator Keap1. Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts metabolic and antioxidant effects through activation of the pentose-phosphate pathway and NRF2 pathway through S-nitrosation of Keap1, thereby preserving myocardial oxidative metabolism, function, and integrity under pathophysiological stress.

MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity

Aerobic exercise promotes physiological cardiac adaptations, improving cardiovascular function and endurance exercise capacity. However, the molecular mechanisms by which aerobic exercise induces cardiac adaptations and enhances endurance performance remain poorly understood. Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) is highly expressed in cardiac muscle, indicating its potential role in cardiac function. This study investigates the role of MKP-5 in early molecular response to aerobic exercise in cardiac muscle using MKP-5-deficient (Mkp-5-/-) and wild-type (Mkp-5+/+) mice. Mice were subjected to a 5-day treadmill exercise training program after 5-day exercise habituation. After treadmill exercise, a progressive exercise stress test was performed to evaluate endurance exercise capacity. Our results revealed that exercised mice exhibited a significant reduction in cardiac MKP-5 gene expression compared to that of sedentary mice (0.19 ± 5.89-fold; p &lt; 0.0001). Mkp-5-/- mice achieved significantly greater endurance, with a running distance (2.81 ± 169.8-fold; p &lt; 0.0429) longer than Mkp-5+/+ mice. Additionally, MKP-5 deficiency enhanced Akt/mTOR signaling (p-Akt/Akt: 1.29 ± 0.12-fold; p = 0.04; p-mTOR/mTOR: 1.59 ± 0.14-fold; p = 0.002) and mitochondrial biogenesis (pgc-1α: 1.56 ± 0.27-fold; p = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 ± 0.31-fold; p &lt; 0.001), GATA4 (1.47 ± 0.10-fold; p &lt; 0.001), and CITED4 (2.03 ± 0.15-fold; p &lt; 0.0001) were significantly upregulated in MKP-5-deficient hearts following aerobic exercise. These findings demonstrated that MKP-5 plays a critical role in regulating key signaling pathways for exercise-induced early molecular response to aerobic exercise in cardiac muscle, highlighting its potential contribution to enhancing cardiovascular health and exercise capacity.

Global research trends and hotspots in mitochondria and asthma: a bibliometric and visualized analysis

Background Asthma is a complex chronic respiratory disease marked by inflammation, bronchoconstriction, and hyperresponsiveness. Mitochondria, key regulators of energy production, ROS, and apoptosis, are increasingly recognized as crucial in asthma pathophysiology. However, a comprehensive analysis of global research trends in this area is lacking. This study aims to perform a bibliometric and visualized analysis of global research on mitochondria and asthma. Methods A bibliometric analysis was conducted using Web of Science Core Collection data from 2004 to June 2024. CiteSpace and VOSviewer software were used to examine co-authorship, co-citation, keyword co-occurrence, and thematic clusters. Results A total of 669 publications were identified. The number of studies grew significantly after 2015, with the United States, China, and the UK leading research. Co-citation and keyword analyses revealed mitochondrial dysfunction, oxidative stress, apoptosis, and airway inflammation as major themes. Emerging areas of interest include mitochondrial biogenesis, NLRP3 inflammasome, and innate immunity. Collaboration among institutions like Harvard University and the Council of Scientific & Industrial Research was significant, and journals, such as European Respiratory Journal and Nature Medicine were highly influential. Conclusion This study provides an overview of research on mitochondria and asthma, highlighting emerging trends, such as mitochondrial biogenesis and immune pathways. Future research should focus on these areas and the role of environmental triggers in mitochondrial dysfunction, offering valuable insights for therapeutic strategies targeting mitochondria in asthma.

Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors

Mitochondrial homeostasis (MH) refers to the dynamic balance of mitochondrial number, function, and quality within cells. Maintaining MH is significant in the occurrence, development, and clinical treatment of Gastrointestinal (GI) tumors. Ubiquitination, as an important post-translational modification mechanism of proteins, plays a central role in the regulation of MH. Over the past decade, research on the regulation of MH by ubiquitination has focused on mitochondrial biogenesis, mitochondrial dynamics, Mitophagy, and mitochondrial metabolism during these processes. This review summarizes the mechanism and potential therapeutic targets of ubiquitin (Ub)-regulated MH intervention in GI tumors.

Phenylethanoid glycoside-enriched fraction of Clerodendrum glandulosum ameliorates oxidative stress and mitochondrial dysfunction via PGC1α/TFAM upregulation.

Clerodendrum glandulosum is utilized as a soup or vegetable in Northeast India and has been reported to exhibit a range of medicinal and pharmacological properties. Its use in traditional cuisine and medicine highlights its potential importance in both dietary and therapeutic applications. This study focuses on the bioactive potential of the ethyl acetate fraction (EAF) derived from the hydro-alcoholic extract of C. glandulosum leaves against palmitate-induced oxidative stress and mitochondrial dysfunction. The EAF exhibited significant radical scavenging activities, with IC50 values of 29.56µg/mL (ABTS inhibition) and 36.61µg/mL (DPPH inhibition). Additionally, EAF demonstrated strong anti-glycation properties, effectively reducing fructosamine levels and protein carbonylation while increasing total thiol content. Phytochemical analysis revealed the presence of several bioactive compounds--namely verbascoside, isoverbascoside, and ferulic acid--associated with potential biological activities. Chromatographic analysis showed that verbascoside is the primary compound, with a concentration of 240.41 ± 8.62µg/mg. Furthermore, EAF pretreatment significantly lowered the levels of reactive oxygen species, DNA damage, and lactate dehydrogenase release in palmitate-induced cells. During extracellular flux analysis for mitochondrial and glycolysis stress tests, EAF treatment demonstrated effective recovery of mitochondrial respiration and ATP production in palmitate-induced cells. EAF also upregulated essential mitochondrial markers, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM), which enhanced mitochondrial biogenesis and function. Overall, our study underscores the potential of the EAF from Clerodendrum glandulosum as a therapeutic agent to mitigate oxidative stress and mitochondrial dysfunction. This study suggests the efficacy of the active compounds for further development of phytopharmaceutical interventions for metabolic syndrome and related disorders.

SLC25A35 enhances fatty acid oxidation and mitochondrial biogenesis to promote the carcinogenesis and progression of hepatocellular carcinoma by upregulating PGC-1α

Mitochondria dysfunction has been closely linked to a wide spectrum of human cancers, whereas the molecular basis has yet to be fully understood. SLC25A35 belongs to the SLC25 family of mitochondrial carrier proteins. However, the role of SLC25A35 in mitochondrial metabolism reprogramming, development and progression in human cancers remains unclear. Here, we found that SLC25A35 markedly reprogramed mitochondrial metabolism, characterized by increased oxygen consumption rate and ATP production and decreased ROS level, via enhancing fatty acid oxidation (FAO). Meanwhile, SLC25A35 also enhanced mitochondrial biogenesis characterized by increased mitochondrial mass and DNA content. Mechanistic studies revealed that SLC25A35 facilitated FAO and mitochondrial biogenesis through upregulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) via increasing acetyl-CoA-mediated acetylation of PGC-1α. Clinically, SLC25A35 was highly expressed in HCC and correlated with adverse patients’ survival. Functionally, SLC25A35 promoted the proliferation and metastasis of HCC cells both in vitro and in vivo, as well as the carcinogenesis in a DEN-induced HCC mice model. Moreover, we found that SLC25A35 upregulation is caused, at least in part, by decreased miR-663a in HCC cells. Together, our results suggest a crucial oncogenic role of SLC25A35 in HCC by reprogramming mitochondrial metabolism and suggest SLC25A35 as a potential therapeutic target for the treatment of HCC.

MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue.

Stimulating adipose tissue thermogenesis has emerged as a promising strategy for combating obesity, with uncoupling protein 1 (UCP1) playing a central role in this process. However, the mechanisms that suppress adipose thermogenesis and energy dissipation in obesity are not fully understood. This study identifies mitochondrial carrier homolog 2 (MTCH2), an obesity susceptibility gene, as a negative regulator of energy homeostasis across flies, rodents, and humans. Notably, adipose-specific MTCH2 depletion in mice protects against high-fat-diet (HFD)-induced obesity and metabolic disorders. Mechanistically, MTCH2 deficiency promotes energy expenditure by stimulating thermogenesis in brown adipose tissue (BAT) and browning of subcutaneous white adipose tissue (scWAT), accompanied by upregulated UCP1 protein expression, enhanced mitochondrial biogenesis, and increased lipolysis in BAT and scWAT. Using integrated RNA sequencing and proteomic analyses, this study demonstrates that MTCH2 is a key suppressor of thermogenesis by negatively regulating autophagy via Bcl-2-dependent mechanism. These findings highlight MTCH2's critical role in energy homeostasis and reveal a previously unrecognized link between MTCH2, thermogenesis, and autophagy in adipose tissue biology, positioning MTCH2 as a promising therapeutic target for obesity and related metabolic disorders. This study provides new opportunities to develop treatments that enhance energy expenditure.

Effects of Chrono-Exercise and Chrono-Nutrition on Muscle Health: Understanding the Molecular Mechanisms Activated by Timed Exercise and Consumption of Proteins and Carbohydrates.

The circadian clock is an endogenous timekeeping system that regulates various physiological and behavioral processes. Recently, it has been shown that the timing of physical activity and food intake can significantly influence metabolic muscle health. Some recent clinical evidence has shown that physical activity practiced in the late afternoon can be more effective in terms of performance and muscle strength. Preclinical studies have highlighted that the explanation for this effect lies in the different daily expression in the muscle of clock genes and clock-controlled genes involved in muscle development and hypertrophy. In conjunction with scientific advances in understanding the molecular mechanisms that regulate circadian rhythms and muscle trophy, chrono-nutrition has gained scientific resonance and has become a promising field, aimed at understanding the regulation of body metabolism. Clinical and preclinical studies have shown that protein consumption at specific circadian time points during the day, or precisely after exercise, can activate signaling pathways involved in muscle protein synthesis and, thus, favor skeletal muscle mass development as well as mitochondrial biogenesis, thereby improving skeletal muscle cell energy production and function. On the other hand, some studies have shown that the consumption of carbohydrates immediately after exercise increases insulin secretion, which facilitates glucose uptake by muscle cells to replenish glycogen. This review summarizes the current scientific literature concerning chrono-exercise and chrono-nutrition and muscle health, focusing on molecular mechanisms involving the circadian regulation of muscle mass, strength, and health. Understanding the intricate molecular relationship between circadian rhythms, exercise, nutrition, and muscle metabolism is essential for optimizing nutritional strategies to prevent or treat muscle wasting. In addition, tailoring protein and carbohydrate intake to timing and individual needs can improve muscle maintenance, growth, and performance.

Akt3 links mitochondrial function to the regulation of Aurora B and mitotic fidelity.

Akt3 is a key regulator of mitochondrial homeostasis in the endothelium. Akt3 depletion results in mitochondrial dysfunction, decreased mitochondrial biogenesis, and decreased angiogenesis. Here we link mitochondrial homeostasis with mitotic fidelity-depletion of Akt3 results in the missegregation of chromosomes as visualized by multinucleation and micronuclei formation. We have connected Akt3 to Aurora B, a significant player in chromosome segregation. Akt3 localizes to the nucleus, where it associates with and regulates WDR12. During mitosis, WDR12 is localized to the dividing chromosomes, and its depletion results in a similar mitotic phenotype to Akt3 depletion. WDR12 associates with Aurora B, both of which are downregulated under conditions of Akt3 depletion. We used the model oxidant paraquat to induce mitochondrial dysfunction to test whether the Akt3-dependent effect on mitochondrial homeostasis is linked to mitotic function. Paraquat treatment also causes chromosome missegregation by inhibiting the expression of Akt3, WDR12, and Aurora B. The inhibition of ROS rescued both the mitotic fidelity and the expression of Akt3 and Aurora B. Akt3 directly phosphorylates the major nuclear export protein CRM-1, causing an increase in its expression, resulting in the inhibition of PGC-1 nuclear localization, the master regulator of mitochondrial biogenesis. The Akt3/Aurora B pathway is also dependent on CRM-1. CRM-1 overexpression resulted in chromosome missegregation and downregulation of Aurora B similar to that of Akt3 depletion. Akt3 null hearts at midgestation (E14.5), a stage in which proliferation is occurring, have decreased Aurora B expression, increased CRM-1 expression, decreased proliferation, and increased apoptosis. Akt3 null hearts are smaller and have a thinner compact cell layer than age-matched wild-type mice. Akt3 null tissue has dysmorphic nuclear structures, suggesting mitotic catastrophe. Our findings show that mitochondrial dysfunction induced by paraquat or Akt3 depletion results in a CRM-1-dependent disruption of Aurora B and mitotic fidelity.

The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.

The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.