Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.

Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.

Fucoidan Improves D-Galactose-Induced Cognitive Dysfunction by Promoting Mitochondrial Biogenesis and Maintaining Gut Microbiome Homeostasis.

Recent studies have indicated that fucoidan has the potential to improve cognitive impairment. The objective of this study was to demonstrate the protective effect and possible mechanisms of fucoidan in D-galactose (D-gal)-induced cognitive dysfunction. Sprague Dawley rats were injected with D-galactose (200 mg/kg, sc) and administrated with fucoidan (100 mg/kg or 200 mg/kg, ig) for 8 weeks. Our results suggested that fucoidan significantly ameliorated cognitive impairment in D-gal-exposed rats and reversed histopathological changes in the hippocampus. Fucoidan reduced D-gal-induced oxidative stress, declined the inflammation level and improved mitochondrial dysfunction in hippocampal. Fucoidan promoted mitochondrial biogenesis by regulating the PGC-1α/NRF1/TFAM pathway, thereby improving D-gal-induced mitochondrial dysfunction. The regulation effect of fucoidan on PGC-1α is linked to the upstream protein of APN/AMPK/SIRT1. Additionally, the neuroprotective action of fucoidan could be related to maintaining intestinal flora homeostasis with up-regulation of Bacteroidota, Muribaculaceae and Akkermansia and down-regulation of Firmicutes. In summary, fucoidan may be a natural, promising candidate active ingredient for age-related cognitive impairment interventions.

Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.

Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) critically utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity.

Serine synthesis controls mitochondrial biogenesis in macrophages.

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis.

BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Saururus chinensis (Lour.) Baill. extract promotes skeletal muscle cell differentiation by positively regulating mitochondrial biogenesis and AKT/mTOR signaling in vitro.

Promotion of myoblast differentiation by activating mitochondrial biogenesis and protein synthesis signaling pathways provides a potential alternative strategy to balance energy and overcome muscle loss and muscle disorders. Saururus chinensis (Lour.) Baill. extract (SCE) has been used extensively as a traditional herbal medicine and has several physiological activities, including anti­asthmatic, anti­oxidant, anti­inflammatory, anti­atopic, anticancer and hepatoprotective properties. However, the effects and mechanisms of action of SCE on muscle differentiation have not yet been clarified. In the present study, it was investigated whether SCE affects skeletal muscle cell differentiation through the regulation of mitochondrial biogenesis and protein synthesis in murine C2C12 myoblasts. The XTT colorimetric assay was used to determine cell viability, and myosin heavy chain (MyHC) levels were determined using immunocytochemistry. SCE was applied to C2C12 myotube at different concentrations (1, 5, or 10 ng/ml) and times (1,3, or 5 days). Reverse transcription­quantitative PCR and western blotting were used to analyze the mRNA and protein expression change of factors related to differentiation, mitochondrial biogenesis and protein synthesis. Treatment of C2C12 cells with SCE at 1,5, and 10 ng/ml did not affect cell viability. SCE promoted C2C12 myotube formation and significantly increased MyHC expression in a concentration­ and time­dependent manner. SCE significantly increased the mRNA and protein expression of muscle differentiation­specific markers, such as MyHC, myogenic differentiation 1, myogenin, Myogenic Factor 5, and ß­catenin, mitochondrial biosynthesis­related factors, such as peroxisome proliferator­activated receptor­gamma coactivator­1α, nuclear respirator factor­1, AMP­activated protein kinase phosphorylation, and histone deacetylase 5 and AKT/mTOR signaling factors related to protein synthesis. SCE may prevent skeletal muscle dysfunction by enhancing myoblast differentiation through the promotion of mitochondrial biogenesis and protein synthesis.

Crucial role of SWL1 in chloroplast biogenesis and development in Arabidopsis thaliana.

KEY MESSAGE: The disruption of the SWL1 gene leads to a significant down regulation of chloroplast and secondary metabolites gene expression in Arabidopsis thaliana. And finally results in a dysfunction of chloroplast and plant growth. Although the development of the chloroplast has been a consistent focus of research, the corresponding regulatory mechanisms remain unidentified. In this study, the CRISPR/Cas9 system was used to mutate the SWL1 gene, resulting in albino cotyledons and variegated true leaf phenotype. Confocal microscopy and western blot of chloroplast protein fractions revealed that SWL1 localized in the chloroplast stroma. Electron microscopy indicated chloroplasts in the cotyledons of swl1 lack well-defined grana and internal membrane structures, and similar structures have been detected in the albino region of variegated true leaves. Transcriptome analysis revealed that down regulation of chloroplast and nuclear gene expression related to chloroplast, including light harvesting complexes, porphyrin, chlorophyll metabolism and carbon metabolism in the swl1 compared to wild-type plant. In addition, proteomic analysis combined with western blot analysis, showed that a significant decrease in chloroplast proteins of swl1. Furthermore, the expression of genes associated with secondary metabolites and growth hormones was also reduced, which may be attributed to SWL1 associated with absorption and fixation of inorganic carbon during chloroplast development. Together, the above findings provide valuable information to elucidate the exact function of SWL1 in chloroplast biogenesis and development.

USP7 cardiomyocyte specific knockout causes disordered mitochondrial biogenesis and dynamics and early neonatal lethality in mice.

BACKGROUND: Ubiquitination is an enzymatic modification involving ubiquitin chains, that can be reversed by deubiquitination (DUB) enzymes. Ubiquitin-specific protease 7 (USP7), which is also known as herpes virus-associated ubiquitin-specific protease (HAUSP), has been shown to play a vital role in cardiovascular diseases. However, the underlying molecular mechanism by which USP7 regulates cardiomyocyte function has not been reported. METHODS: To understand the physiological function of USP7 in the heart, we constructed cardiomyocyte-specific USP7 conditional knockout mice. RESULTS: We found that homozygous knockout mice died approximately three weeks after birth, while heterozygous knockout mice grew normally into adulthood. Severe cardiac dysfunction, hypertrophy, fibrosis, and cell apoptosis were observed in cardiomyocyte-specific USP7 knockout mice, and these effects were accompanied by disordered mitochondrial dynamics and cardiometabolic-related proteins. CONCLUSIONS: In summary, we investigated changes in the growth status and cardiac function of cardiomyocyte-specific USP7 knockout mice, and preliminarily explored the underlying mechanism.

The Effect of Cold-Water Swimming on Energy Metabolism, Dynamics, and Mitochondrial Biogenesis in the Muscles of Aging Rats.

Our study aimed to explore the potential positive effects of cold water exercise on mitochondrial biogenesis and muscle energy metabolism in aging rats. The study involved 32 male and 32 female rats aged 15 months, randomly assigned to control sedentary animals, animals training in cold water at 5 ± 2 °C, or animals training in water at thermal comfort temperature (36 ± 2 °C). The rats underwent swimming training for nine weeks, gradually increasing the duration of the sessions from 2 min to 4 min per day, five days a week. The results demonstrated that swimming in thermally comfortable water improved the energy metabolism of aging rat muscles (increased metabolic rates expressed as increased ATP, ADP concentration, TAN (total adenine nucleotide) and AEC (adenylate energy charge value)) and increased mRNA and protein expression of fusion regulatory proteins. Similarly, cold-water swimming improved muscle energy metabolism in aging rats, as shown by an increase in muscle energy metabolites and enhanced mitochondrial biogenesis and dynamics. It can be concluded that the additive effect of daily activity in cold water influenced both an increase in the rate of energy metabolism in the muscles of the studied animals and an intensification of mitochondrial biogenesis and dynamics (related to fusion and fragmentation processes). Daily activity in warm water also resulted in an increase in the rate of energy metabolism in muscles, but at the same time did not cause significant changes in mitochondrial dynamics.

[Ginsenoside Re regulates mitochondrial biogenesis through Nrf2/HO-1/PGC-1α pathway to reduce hypoxia/reoxygenation injury in H9c2 cells].

This article explored the mechanism by which ginsenoside Re reduces hypoxia/reoxygenation(H/R) injury in H9c2 cells by regulating mitochondrial biogenesis through nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/peroxisome prolife-rator-activated receptor gamma coactivator-1α(PGC-1α) pathway. In this study, H9c2 cells were cultured in hypoxia for 4 hours and then reoxygenated for 2 hours to construct a cardiomyocyte H/R injury model. After ginsenoside Re pre-administration intervention, cell activity, superoxide dismutase(SOD) activity, malondialdehyde(MDA) content, intracellular reactive oxygen species(Cyto-ROS), and intramitochondrial reactive oxygen species(Mito-ROS) levels were detected to evaluate the protective effect of ginsenoside Re on H/R injury of H9c2 cells by resisting oxidative stress. Secondly, fluorescent probes were used to detect changes in mitochondrial membrane potential(ΔΨ_m) and mitochondrial membrane permeability open pore(mPTP), and immunofluorescence was used to detect the expression level of TOM20 to study the protective effect of ginsenoside Re on mitochondria. Western blot was further used to detect the protein expression levels of caspase-3, cleaved caspase-3, Cyto C, Nrf2, HO-1, and PGC-1α to explore the specific mechanism by which ginsenoside Re protected mitochondria against oxidative stress and reduced H/R injury. Compared with the model group, ginse-noside Re effectively reduced the H/R injury oxidative stress response of H9c2 cells, increased SOD activity, reduced MDA content, and decreased Cyto-ROS and Mito-ROS levels in cells. Ginsenoside Re showed a good protective effect on mitochondria by increasing ΔΨ_m, reducing mPTP, and increasing TOM20 expression. Further studies showed that ginsenoside Re promoted the expression of Nrf2, HO-1, and PGC-1α proteins, and reduced the activation of the apoptosis-related regulatory factor caspase-3 to cleaved caspase-3 and the expression of Cyto C protein. In summary, ginsenoside Re can significantly reduce I/R injury in H9c2 cells. The specific mechanism is related to the promotion of mitochondrial biogenesis through the Nrf2/HO-1/PGC-1α pathway, thereby increasing the number of mitochondria, improving mitochondrial function, enhancing the ability of cells to resist oxidative stress, and alleviating cell apoptosis.

Altered Glycolysis, Mitochondrial Biogenesis, Autophagy and Apoptosis in Peritoneal Endometriosis in Adolescents.

Energy metabolism plays a pivotal role in the pathogenesis of endometriosis. For the initial stages of the disease in adolescents, this aspect remains unexplored. The objective of this paper was to analyze the association of cellular and endosomal profiles of markers of glycolysis, mitochondrial biogenesis, apoptosis, autophagy and estrogen signaling in peritoneal endometriosis (PE) in adolescents. We included 60 girls aged 13-17 years in a case-control study: 45 with laparoscopically confirmed PE (main group) and 15 with paramesonephric cysts (comparison group). Samples of plasma and peritoneal fluid exosomes, endometrioid foci and non-affected peritoneum were tested for estrogen receptor (Erα/ß), hexokinase (Hex2), pyruvate dehydrogenase kinase (PDK1), glucose transporter (Glut1), monocarboxylate transporters (MCT1 and MCT2), optic atrophy 1 (OPA1, mitochondrial fusion protein), dynamin-related protein 1 (DRP1, mitochondrial fission protein), Bax, Bcl2, Beclin1, Bnip3, P38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (Hif-1α), mitochondrial voltage-dependent anion channel (VDAC) and transforming growth factor (TGFß) proteins as markers of estrogen signaling, glycolysis rates, mitochondrial biogenesis and damage, apoptosis and autophagy (Western-Blot and PCR). The analysis identified higher levels of molecules associated with proliferation (ERß), glycolysis (MCT2, PDK1, Glut1, Hex2, TGFß and Hif-1α), mitochondrial biogenesis (OPA1, DRP1) and autophagy (P38, Beclin1 and Bnip3) and decreased levels of apoptosis markers (Bcl2/Bax) in endometrioid foci compared to non-affected peritoneum and that in the comparison group (p < 0.05). Patients with PE had altered profiles of ERß in plasma and peritoneal fluid exosomes and higher levels of Glut1, MCT2 and Bnip3 in plasma exosomes (p < 0.05). The results of the differential expression profiles indicate microenvironment modification, mitochondrial biogenesis, estrogen reception activation and glycolytic switch along with apoptosis suppression in peritoneal endometrioid foci already in adolescents.

Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

Isobavachin attenuates osteoclastogenesis and periodontitis-induced bone loss by inhibiting cellular iron accumulation and mitochondrial biogenesis.

As bone-resorbing cells rich in mitochondria, osteoclasts require high iron uptake to promote mitochondrial biogenesis and maintain a high-energy metabolic state for active bone resorption. Given that abnormal osteoclast formation and activation leads to imbalanced bone remodeling and osteolytic bone loss, osteoclasts may be crucial targets for treating osteolytic diseases such as periodontitis. Isobavachin (IBA), a natural flavonoid compound, has been confirmed to be an inhibitor of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs). However, its effects on periodontitis-induced bone loss and the potential mechanism of its anti-osteoclastogenesis effect remain unclear. Our study demonstrated that IBA suppressed RANKL-induced osteoclastogenesis in BMMs and RAW264.7 cells and inhibited osteoclast-mediated bone resorption in vitro. Transcriptomic analysis indicated that iron homeostasis and reactive oxygen species (ROS) metabolic process were enriched among the differentially expressed genes following IBA treatment. IBA exerted its anti-osteoclastogenesis effect by inhibiting iron accumulation in osteoclasts. Mechanistically, IBA attenuated iron accumulation in RANKL-induced osteoclasts by inhibiting the mitogen-activated protein kinase (MAPK) pathway to upregulate ferroportin1 (Fpn1) expression and promote Fpn1-mediated intracellular iron efflux. We also found that IBA inhibited mitochondrial biogenesis and function, and reduced RANKL-induced ROS generation in osteoclasts. Furthermore, IBA attenuated periodontitis-induced bone loss by reducing osteoclastogenesis in vivo. Overall, these results suggest that IBA may serve as a promising therapeutic strategy for bone diseases characterized by osteoclastic bone resorption.

Nicotinamide Mononucleotide (NMN) Works in Type 2 Diabetes through Unexpected Effects in Adipose Tissue, Not by Mitochondrial Biogenesis.

Nicotinamide mononucleotide (NMN) has emerged as a promising therapeutic intervention for age-related disorders, including type 2 diabetes. In this study, we confirmed the previously observed effects of NMN treatment on glucose uptake and investigated its underlying mechanisms in various tissues and cell lines. Through the most comprehensive proteomic analysis to date, we discovered a series of novel organ-specific effects responsible for glucose uptake as measured by the IPGTT: adipose tissue growing (suggested by increased protein synthesis and degradation and mTOR proliferation signaling upregulation). Notably, we observed the upregulation of thermogenic UCP1, promoting enhanced glucose conversion to heat in intermuscular adipose tissue while showing a surprising repressive effect on mitochondrial biogenesis in muscle and the brain. Additionally, liver and muscle cells displayed a unique response, characterized by spliceosome downregulation and concurrent upregulation of chaperones, proteasomes, and ribosomes, leading to mildly impaired and energy-inefficient protein synthesis machinery. Furthermore, our findings revealed remarkable metabolic rewiring in the brain. This involved increased production of ketone bodies, downregulation of mitochondrial OXPHOS and TCA cycle components, as well as the induction of well-known fasting-associated effects. Collectively, our data elucidate the multifaceted nature of NMN action, highlighting its organ-specific effects and their role in improving glucose uptake. These findings deepen our understanding of NMN's therapeutic potential and pave the way for novel strategies in managing metabolic disorders.

Orientin Promotes Antioxidant Capacity, Mitochondrial Biogenesis, and Fiber Transformation in Skeletal Muscles through the AMPK Pathway.

The sleep-breathing condition obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse, which can exacerbate oxidative stress and free radical generation, thereby detrimentally impacting both motor and sensory nerve function and inducing muscular damage. OSA development is promoted by increasing proportions of fast-twitch muscle fibers in the genioglossus. Orientin, a water-soluble dietary C-glycosyl flavonoid with antioxidant properties, increased the expression of slow myosin heavy chain (MyHC) and signaling factors associated with AMP-activated protein kinase (AMPK) activation both in vivo and in vitro. Inhibiting AMPK signaling diminished the effects of orientin on slow MyHC, fast MyHC, and Sirt1 expression. Overall, orientin enhanced type I muscle fibers in the genioglossus, enhanced antioxidant capacity, increased mitochondrial biogenesis through AMPK signaling, and ultimately improved fatigue resistance in C2C12 myotubes and mouse genioglossus. These findings suggest that orientin may contribute to upper airway stability in patients with OSA, potentially preventing airway collapse.

The potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder marked by deficiencies in insulin secretion and/or function, affecting various tissues and organs and leading to numerous complications. Mitochondrial biogenesis, the process by which cells generate new mitochondria utilizing existing ones plays a crucial role in energy homeostasis, glucose metabolism, and lipid handling. Recent evidence suggests that promoting mitochondrial biogenesis can alleviate insulin resistance in the liver, adipose tissue, and skeletal muscle while improving pancreatic ß-cell function. Moreover, enhanced mitochondrial biogenesis has been shown to ameliorate T2DM symptoms and may contribute to therapeutic effects for the treatment of diabetic nephropathy, cardiomyopathy, retinopathy, and neuropathy. This review summarizes the intricate connection between mitochondrial biogenesis and T2DM, highlighting the potential of novel therapeutic strategies targeting mitochondrial biogenesis for T2DM treatment and its associated complications. It also discusses several natural products that exhibit beneficial effects on T2DM by promoting mitochondrial biogenesis.

Nickel induces mitochondrial damage in renal cells in vitro and in vivo through its effects on mitochondrial biogenesis, fusion, and fission.

Nickel (Ni) and its compounds are common, widely distributed components of hazardous waste in the chemical industry. Excessive exposure to Ni can cause kidney damage in humans and animals. We investigated the impact of Ni on renal mitochondria using in vivo and in vitro models of Ni nephrotoxicity, and explored the Ni nephrotoxic mechanism. We showed that nickel chloride (NiCl2) damaged the renal mitochondria, causing mitochondrial swelling, breakage of the mitochondrial cristae, increased levels of mitochondrial reactive oxygen species (mt-ROS), and depolarization of the mitochondrial membrane potential (MMP). The levels of the mitochondrial respiratory chain complexes I-IV were reduced in the kidneys of mice treated with NiCl2. In addition, NiCl2 treatment inhibited mitochondrial biogenesis in renal cells by down-regulating mRNA and the protein expression of TFAM, PGC-1α, and NRF1. Moreover, NiCl2 reduced the levels of the proteins involved in mitochondrial fusion, including Mfn1 and Mfn2, while significantly augmenting the levels of the proteins Fis1 and Drip1 involved in mitochondrial fission in renal cells. Taken together, these results suggested that NiCl2 inhibited mitochondrial biogenesis, suppressed mitochondrial fusion, and promoted mitochondrial fission, resulting in mitochondrial dysfunction in renal cells, ultimately causing renal injury. This study provided novel insights into the mechanisms of nephrotoxicity of Ni and new ideas for the development of targeted treatments for Ni-induced kidney injury.

Mitochondrial dysfunction in the pathophysiology of renal diseases.

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and the unfolded protein response, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the cross talk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondria-related clinical research.

Serotonin regulation of mitochondria in kidney diseases.

Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored.

Heat Shock Protein 22 Attenuates Nerve Injury-induced Neuropathic Pain Via Improving Mitochondrial Biogenesis and Reducing Oxidative Stress Mediated By Spinal AMPK/PGC-1α Pathway in Male Rats.

Heat shock protein 22 (hsp22) plays a significant role in mitochondrial biogenesis and redox balance. Moreover, it's well accepted that the impairment of mitochondrial biogenesis and redox imbalance contributes to the progress of neuropathic pain. However, there is no available evidence indicating that hsp22 can ameliorate mechanical allodynia and thermal hyperalgesia, sustain mitochondrial biogenesis and redox balance in rats with neuropathic pain. In this study, pain behavioral test, western blotting, immunofluorescence staining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Dihydroethidium staining are applied to confirm the role of hsp22 in a male rat model of spared nerve injury (SNI). Our results indicate that hsp22 was significantly decreased in spinal neurons post SNI. Moreover, it was found that intrathecal injection (i.t.) with recombinant heat shock protein 22 protein (rhsp22) ameliorated mechanical allodynia and thermal hyperalgesia, facilitated nuclear respiratory factor 1 (NRF1)/ mitochondrial transcription factor A (TFAM)-dependent mitochondrial biogenesis, decreased the level of reactive oxygen species (ROS), and suppressed oxidative stress via activation of spinal adenosine 5'monophosphate-activated protein kinase (AMPK)/ peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) pathway in male rats with SNI. Furthermore, it was also demonstrated that AMPK antagonist (compound C, CC) or PGC-1α siRNA reversed the improved mechanical allodynia and thermal hyperalgesia, mitochondrial biogenesis, oxidative stress, and the decreased ROS induced by rhsp22 in male rats with SNI. These results revealed that hsp22 alleviated mechanical allodynia and thermal hyperalgesia, improved the impairment of NRF1/TFAM-dependent mitochondrial biogenesis, down-regulated the level of ROS, and mitigated oxidative stress through stimulating the spinal AMPK/PGC-1α pathway in male rats with SNI.