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European Journal of Cell Biology Jan 2021In response to mitochondrial damage, mitochondria activate mitochondrial dynamics to maintain normal functions, and an imbalance in mitochondrial dynamics triggers... (Review)
Review
In response to mitochondrial damage, mitochondria activate mitochondrial dynamics to maintain normal functions, and an imbalance in mitochondrial dynamics triggers multiple programmed cell death processes. Recent studies have shown that phosphoglycerate mutase 5 (PGAM5) is associated with mitochondrial damage. PGAM5 activates mitochondrial biogenesis and mitophagy to promote a cellular compensatory response when mitochondria are mildly damaged, whereas severe damage to mitochondria leads to PGAM5 inducing excessive mitochondria fission, disruption to mitochondrial movement, and amplification of apoptosis, necroptosis and mitophagic death signals, which eventually evoke cell death. PGAM5 functions mainly through protein-protein interactions and specific Ser/Thr/His protein phosphatase activity. PGAM5 is also regulated by mitochondrial proteases. Detection of PGAM5 and its interacting protein partners should enable a more accurate evaluation of mitochondrial damage and a more precise method for the diagnosis and treatment of diseases.
Topics: Apoptosis; Humans; Mitochondrial Dynamics; Mitochondrial Proteins; Mitophagy; Necroptosis; Phosphoprotein Phosphatases
PubMed: 33370650
DOI: 10.1016/j.ejcb.2020.151144 -
Journal of Translational Medicine Oct 2022Adipose tissue-derived adipokines are involved in various crosstalk between adipose tissue and other organs. Omentin1, a novel adipokine, exerts vital roles in the...
BACKGROUND
Adipose tissue-derived adipokines are involved in various crosstalk between adipose tissue and other organs. Omentin1, a novel adipokine, exerts vital roles in the maintenance of body metabolism, insulin resistance and the like. However, the protective effect of omentin1 in myocardial ischemia (MI)-induced heart failure (HF) and its specific mechanism remains unclear and to be elucidated.
METHODS
The model of MI-induced HF mice and oxygen glucose deprivation (OGD)-injured cardiomyocytes were performed. Mice with overexpression of omentin1 were constructed by a fat-specific adeno-associated virus (AAV) vector system.
RESULTS
We demonstrated that circulating omentin1 level diminished in HF patients compared with healthy subjects. Furthermore, the fat-specific overexpression of omentin1 ameliorated cardiac function, cardiac hypertrophy, infarct size and cardiac pathological features, and also enhanced SIRT3/FOXO3a signaling in HF mice. Additionally, administration with AAV-omentin1 increased mitochondrial fusion and decreased mitochondrial fission in HF mice, as evidenced by up-regulated expression of Mfn2 and OPA1, and downregulation of p-Drp1(Ser616). Then, it also promoted PINK1/Parkin-dependent mitophagy. Simultaneously, treatment with recombinant omentin1 strengthened OGD-injured cardiomyocyte viability, restrained LDH release, and enhanced the mitochondrial accumulation of SIRT3 and nucleus transduction of FOXO3a. Besides, omentin1 also ameliorated unbalanced mitochondrial fusion-fission dynamics and activated mitophagy, thereby, improving the damaged mitochondria morphology and controlling mitochondrial quality in OGD-injured cardiomyocytes. Interestingly, SIRT3 played an important role in the improvement effects of omentin1 on mitochondrial function, unbalanced mitochondrial fusion-fission dynamics and mitophagy.
CONCLUSION
Omentin1 improves MI-induced HF and myocardial injury by maintaining mitochondrial dynamical homeostasis and activating mitophagy via upregulation of SIRT3/FOXO3a signaling. This study provides evidence for further application of omentin1 in cardiovascular diseases from the perspective of crosstalk between heart and adipose tissue.
Topics: Adipokines; Animals; Cytokines; GPI-Linked Proteins; Glucose; Heart Failure; Homeostasis; Lectins; Mice; Mitochondrial Dynamics; Mitophagy; Myocardial Ischemia; Oxygen; Protein Kinases; Sirtuin 3; Ubiquitin-Protein Ligases
PubMed: 36192726
DOI: 10.1186/s12967-022-03642-x -
Proceedings of the National Academy of... Aug 2022Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and...
Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
Topics: Cell Respiration; GTP Phosphohydrolases; Gene Expression; Mitochondria; Mitochondrial Dynamics; Protein Kinases
PubMed: 35969774
DOI: 10.1073/pnas.2120157119 -
International Journal of Oral Science Sep 2021Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite...
Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite mechanisms remain elusive. Emerging evidence supports an association between mitochondrial dysfunction and AS. In our study, the impact of P. gingivalis on mitochondrial dysfunction and the potential mechanism were investigated. The mitochondrial morphology of EA.hy926 cells infected with P. gingivalis was assessed by transmission electron microscopy, mitochondrial staining, and quantitative analysis of the mitochondrial network. Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP) levels. Cellular ATP production was examined by a luminescence assay kit. The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence. Mdivi-1, a specific Drp1 inhibitor, was used to elucidate the role of Drp1 in mitochondrial dysfunction. Our findings showed that P. gingivalis infection induced mitochondrial fragmentation, increased the mtROS levels, and decreased the MMP and ATP concentration in vascular endothelial cells. We observed upregulation of Drp1 (Ser616) phosphorylation and translocation of Drp1 to mitochondria. Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P. gingivalis. Collectively, these results revealed that P. gingivalis infection promoted mitochondrial fragmentation and dysfunction, which was dependent on Drp1. Mitochondrial dysfunction may represent the mechanism by which P. gingivalis exacerbates atherosclerotic lesions.
Topics: Endothelial Cells; Mitochondria; Mitochondrial Dynamics; Porphyromonas gingivalis
PubMed: 34475379
DOI: 10.1038/s41368-021-00134-4 -
Cell Cycle (Georgetown, Tex.) 2018Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer.... (Review)
Review
Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation. Mitostemness traits, namely mitonuclear communication, mitoproteome components, and mitochondrial fission/fusion dynamics, can be therapeutically exploited to target the CSC state. We briefly review the pre-clinical evidence of action of investigational compounds on mitostemness traits and discuss ongoing strategies to accelerate the clinical translation of new mitostemness drugs. The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena may open up a new therapeutic dimension against life-threatening CSCs. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.
Topics: Antineoplastic Agents; Bacteria; Cell Nucleus; Humans; Mitochondria; Mitochondrial Dynamics; Neoplastic Stem Cells
PubMed: 29886796
DOI: 10.1080/15384101.2018.1467679 -
Journal of Pineal Research Sep 2018Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly...
Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes-induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes-induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes-induced cardiac dysfunction by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ)-induced diabetic mice, but not in SIRT1 diabetic mice. In high glucose-exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC-1α and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. In contrast, SIRT1 or PGC-1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1-mediated mitochondrial fission in a SIRT1/PGC-1α-dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi-1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission through SIRT1-PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.
Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dynamins; Melatonin; Mice; Mice, Knockout; Mitochondria, Heart; Mitochondrial Dynamics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Sirtuin 1
PubMed: 29575122
DOI: 10.1111/jpi.12491 -
Osteoarthritis and Cartilage Feb 2022To determine the Dynamin-related protein 1 (DRP1) regulation of mitochondrial fission in chondrocytes under pathological conditions, an area which is underexplored in...
OBJECTIVE
To determine the Dynamin-related protein 1 (DRP1) regulation of mitochondrial fission in chondrocytes under pathological conditions, an area which is underexplored in osteoarthritis pathogenesis.
DESIGN
DRP1 protein expression was determined by immunohistochemistry (IHC) or immunofluorescence (IF) staining of cartilage sections. IL-1β-induced DRP1 mRNA expression in chondrocytes was quantified by qPCR and protein expression by immunoblotting. Mitochondrial fragmentation in chondrocytes was visualized by MitoTracker staining or IF staining of mitochondrial marker proteins or by transient expression of mitoDsRed. Mitochondrial reactive oxygen species (ROS) levels were determined by MitoSOX staining. Apoptosis was determined by lactate dehydrogenase (LDH) release assay, Caspase 3/7 activity assay, propidium iodide (PI), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and IF staining of cleaved caspase 3. Cytochrome c release was determined by confocal microscopy. Surgical destabilization of the medial meniscus (DMM) was used to induce osteoarthritis (OA) in mice.
RESULTS
Expression of DRP1 and mitochondrial damage was high in human OA cartilage and in the joints of mice subjected to DMM surgery which also showed increased chondrocytes apoptosis. IL-1β-induced mitochondrial network fragmentation and chondrocyte apoptosis via modulation of DRP1 expression and activity and induce apoptosis via Bax-mediated release of Cytochrome c. Pharmacological inhibition of DRP1 activity by Mdivi-1 blocked IL-1β-induced mitochondrial damage and apoptosis in chondrocytes. Additionally, IL-1β-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) is crucial for DRP1 activation and induction of mitochondrial network fragmentation in chondrocytes as these were blocked by inhibiting ERK1/2 activation.
CONCLUSIONS
These findings demonstrate that ERK1/2 is a critical player in DRP1-mediated induction of mitochondrial fission and apoptosis in IL-1β-stimulated chondrocytes.
Topics: Aged; Animals; Apoptosis; Chondrocytes; Dynamins; Female; Humans; MAP Kinase Signaling System; Male; Mice; Middle Aged; Mitochondrial Dynamics
PubMed: 34767958
DOI: 10.1016/j.joca.2021.11.003 -
Molecular Cell Sep 2021Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show...
Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.
Topics: AMP-Activated Protein Kinases; Animals; Cell Line; Humans; Inositol; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Dynamics; PC-3 Cells; Phosphoric Monoester Hydrolases; Phosphorylation; Stress, Physiological
PubMed: 34547240
DOI: 10.1016/j.molcel.2021.08.025 -
Proceedings of the National Academy of... Jan 2023Exercise is a nonpharmacological intervention that improves health during aging and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise...
Exercise is a nonpharmacological intervention that improves health during aging and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size, and function. Here we have investigated the role of mitochondrial dynamics during exercise in the model organism . We show that in body-wall muscle, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and physical fitness decline that occur with aging. Maintenance of proper mitochondrial dynamics is essential for physical fitness, its enhancement by exercise training, and exercise-induced remodeling of the proteome. Surprisingly, among the long-lived genotypes we analyzed (,, , , and ), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves physical fitness during aging, a benefit that is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for physical fitness to be enhanced by exercise, with our findings together suggesting that exercise may enhance muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining physical fitness and exercise responsiveness during aging and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging.
Topics: Animals; Mitochondrial Dynamics; AMP-Activated Protein Kinases; Aging; Caenorhabditis elegans; Exercise; Physical Fitness; Muscle, Skeletal
PubMed: 36595699
DOI: 10.1073/pnas.2204750120 -
Cancer Communications (London, England) Jan 2022Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes. Recently, abnormally increased mitochondrial fission...
BACKGROUND
Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes. Recently, abnormally increased mitochondrial fission has been observed in several types of cancer. However, the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear. This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepatocellular carcinoma (HCC) cells.
METHODS
Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content. The rate of fatty acid oxidation was evaluated by [ H]-labelled oleic acid. The mitochondrial morphology in HCC cells was evaluated by fluorescent staining. The expression of protein was determined by real-time PCR, iimmunohistochemistry and Western blotting.
RESULTS
Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase (FASN), acetyl-CoA carboxylase1 (ACC1), and elongation of very long chain fatty acid protein 6 (ELOVL6), while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1). Consistently, suppressed mitochondrial fission exhibited the opposite effects. Moreover, in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells. Mechanistically, mitochondrial fission increased the acetylation level of sterol regulatory element-binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) by suppressing nicotinamide adenine dinucleotide (NAD+)/Sirtuin 1 (SIRT1) signaling. The elevated SREBP1 then upregulated the expression of FASN, ACC1 and ELOVL6 in HCC cells, while PGC-1α/PPARα suppressed the expression of CPT1A and ACOX1.
CONCLUSIONS
Increased mitochondrial fission plays a crucial role in the reprogramming of lipid metabolism in HCC cells, which provides strong evidence for the use of this process as a drug target in the treatment of this malignancy.
Topics: Carcinoma, Hepatocellular; Fatty Acids; Humans; Lipid Metabolism; Liver Neoplasms; Mitochondrial Dynamics; Sirtuin 1
PubMed: 34981667
DOI: 10.1002/cac2.12247