bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒12‒17
sixteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
  2. The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
  3. Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
  4. Protein import into mitochondria - a new path through the membranes.
  5. Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
  6. NOX4 alleviates breast cancer cell aggressiveness by co-ordinating mitochondrial turnover through PGC1α/Drp1 axis.
  7. Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove.
  8. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  9. Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
  10. Mitochondrial temperature homeostasis resists external metabolic stresses.
  11. Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.
  12. The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
  13. CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
  14. Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
  15. The critical roles of STING in mitochondrial homeostasis.
  16. The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
  1. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120
    The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
    Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.
      The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.
    Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis
    DOI:  https://doi.org/10.1073/pnas.2303713120
  2. Nat Commun. 2023 Dec 12. 14(1): 8248
    The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
    Lindsay McGregor, Samira Acajjaoui, Ambroise Desfosses, Melissa Saïdi, Maria Bacia-Verloop, Jennifer J Schwarz, Pauline Juyoux, Jill von Velsen, Matthew W Bowler, Andrew A McCarthy, Eaazhisai Kandiah, Irina Gutsche, Montserrat Soler-Lopez.
      The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.
    DOI:  https://doi.org/10.1038/s41467-023-43865-0
  3. Nat Commun. 2023 Dec 08. 14(1): 8115
    Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
    Helene Jahn, Ladislav Bartoš, Grace I Dearden, Jeremy S Dittman, Joost C M Holthuis, Robert Vácha, Anant K Menon.
      Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.
    DOI:  https://doi.org/10.1038/s41467-023-43570-y
  4. Nat Struct Mol Biol. 2023 Dec;30(12): 1831-1833
    Protein import into mitochondria - a new path through the membranes.
    Michal Wasilewski, Piotr Draczkowski, Agnieszka Chacinska.
      
    DOI:  https://doi.org/10.1038/s41594-023-01170-w
  5. J Clin Invest. 2023 Dec 07. pii: e162533. [Epub ahead of print]
    Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
    Spencer Greatorex, Supreet Kaur, Chrysovalantou E Xirouchaki, Pei Kee Goh, Florian Wiede, Amanda J Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A Brown, Catriona A McLean, Junichi Sadoshima, Matthew J Watt, Tony Tiganis.
      Non-alcoholic fatty liver disease (NAFLD) is prevalent in the majority of obese individuals, but in a subset, this progresses to non-alcoholic steatohepatitis (NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of NAFLD patients remain unclear. Here we report that NAD(P)H oxidase (NOX)-4 and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH/fibrosis. Mitochondrial-derived reactive oxygen species (ROS) activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signalling and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high fat fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH/fibrosis in mice fed a NASH-promoting diet. Thus, mitochondrial- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and the progression to NASH/fibrosis in obesity.
    Keywords:  Diabetes; Glucose metabolism; Hepatology; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI162533
  6. Cell Signal. 2023 Dec 11. pii: S0898-6568(23)00423-0. [Epub ahead of print] 111008
    NOX4 alleviates breast cancer cell aggressiveness by co-ordinating mitochondrial turnover through PGC1α/Drp1 axis.
    Deepali Bhadane, Dinisha Kamble, Mangesh Deval, Subhajit Das, Sandhya Sitasawad.
      Triple Negative Breast Cancer (TNBC) is a highly aggressive form of breast cancer, with few treatment options. This study investigates the complex molecular mechanism by which NADPH oxidase 4 (NOX4), a major ROS producer in mitochondria, affects the aggressiveness of luminal and triple-negative breast cancer cells (TNBCs). We found that NOX4 expression was differentially regulated in luminal and TNBC cells, with a positive correlation to their epithelial characteristics. Time dependent analysis revealed that TNBCs exhibits higher steady-state ROS levels than luminal cells, but NOX4 silencing increased ROS levels in luminal breast cancer cells and enhanced their ability to migrate and invade. In contrast, NOX4 over expression in TNBCs had the opposite effect. The mouse tail-vein experiment showed that the group injected with NOX4 silenced luminal cells had a higher number of lung metastases compared to the control group. Mechanistically, NOX4 enhanced PGC1α dependent mitochondrial biogenesis and attenuated Drp1-mediated mitochondrial fission in luminal breast cancer cells, leading to an increased mitochondrial mass and elongated mitochondrial morphology. Interestingly, NOX4 silencing increased mitochondrial ROS (mtROS) levels without affecting mitochondrial (Δψm) and cellular integrity. Inhibition of Drp1-dependent fission with Mdivi1 reversed the effect of NOX4-dependent mitochondrial biogenesis, dynamics, and migration of breast cancer cells. Our findings suggest that NOX4 expression diminishes from luminal to a triple negative state, accompanied by elevated ROS levels, which may modulate mitochondrial turnover to attain an aggressive phenotype. The study provides potential insights for targeted therapies for TNBCs.
    Keywords:  Breast cancer aggressiveness; Drp1; NOX4; PGC1α; ROS; TNBC
    DOI:  https://doi.org/10.1016/j.cellsig.2023.111008
  7. Commun Biol. 2023 Dec 12. 6(1): 1260
    Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove.
    Peng Cheng, Yuzhu Hou, Mingxing Bian, Xueru Fang, Yan Liu, Yuanfang Rao, Shuo Cao, Yanjun Liu, Shuai Zhang, Yanke Chen, Xu Dong, Zhu Liu.
      BAK permeabilizes the mitochondrial outer membrane, causing apoptosis. This apoptotic activity of BAK is stimulated by binding prodeath activators within its canonical hydrophobic groove. Parkin, an E3 ubiquitin (Ub) ligase, can ubiquitinate BAK, which inhibits BAK apoptotic activity. However, the molecular mechanism underlying the inhibition of ubiquitination remains structurally uncharacterized. Here, we utilize truncated and soluble BAK to construct a mimetic of K113-ubiquitinated BAK (disulfide-linked UbG76C ~ BAKK113C) and further present its NMR-derived structure model. The classical L8-I44-H68-V70 hydrophobic patch of the conjugated Ub subunit binds within the canonical hydrophobic groove of BAK. This Ub occludes the binding of prodeath BID activators in the groove and impairs BID-triggered BAK activation and membrane permeabilization. Reduced interaction between Ub and BAK subunits allows BID to activate K113-ubiquitinated BAK. These mechanistic insights suggest a nonsignaling function of Ub in that it directly antagonizes stimuli targeting Ub-modified proteins rather than by recruiting downstream partners for cellular messaging.
    DOI:  https://doi.org/10.1038/s42003-023-05650-z
  8. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  9. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2316823120
    Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.
    Wenzhang Wang, Xiaopin Ma, Sabina Bhatta, Changjuan Shao, Fanpeng Zhao, Hisashi Fujioka, Sandy Torres, Fengqin Wu, Xiongwei Zhu.
      Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.
    Keywords:  Alzheimer’s disease; Aβ42; LONP1; mitochondrial dysfunction; protein aggregate
    DOI:  https://doi.org/10.1073/pnas.2316823120
  10. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  11. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 12.
    Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.
    Debanjali Dasgupta, Sanjana Mahadev Bhat, Claire Creighton, Catherin Cortes, Philippe F Delmotte, Gary C Sieck.
      Tumor necrosis factor α (TNFa), a proinflammatory cytokine, plays a significant role in mediating the effects of acute inflammation in response to allergens, pollutants, and respiratory infections. Previously, we showed that acute exposure to TNFa induces mitochondrial fragmentation in human airway smooth muscle (hASM) cells, which is associated with increased expression of dynamin-related protein 1 (DRP1). Phosphorylation of DRP1 at serine 616 (pDRP1S616) promotes its translocation and binding to the outer mitochondrial membrane (OMM) and mediates mitochondrial fragmentation. Previously, we reported that TNFa exposure triggers protein unfolding and triggers an endoplasmic reticulum (ER) stress response involving phosphorylation of inositol-requiring enzyme 1α (pIRE1a) at serine 724 (pIRE1aS724) and subsequent splicing of X-box binding protein 1 (XBP1s) in hASM cells. We hypothesize that TNFa-mediated activation of the pIRE1aS724/XBP1s ER stress pathway in hASM cells transcriptionally activates genes that encode kinases responsible for pDRP1S616 phosphorylation. Using 3-D confocal imaging of MitoTracker green-labeled mitochondria, we found that TNFa treatment for 6 h induces mitochondrial fragmentation in hASM cells. We also confirmed that 6 h TNFa treatment activates the pIRE1a/XBP1s ER stress pathway. Using in silico analysis and ChIP assay, we showed that CDK1 and CDK5, kinases involved in the phosphorylation of pDRP1S616, are transcriptionally targeted by XBP1s. TNFa treatment increased the binding affinity of XBP1s on the promoter regions of CDK1 and CDK5, and this was associated with an increase in pDRP1S616 and mitochondria fragmentation. This study reveals a new underlying molecular mechanism for TNFa-induced mitochondrial fragmentation in hASM cells.
    Keywords:  Airway smooth muscle; DRP1 phosphorylation; ER stress; airway inflammation; mitochondrial fragmentation
    DOI:  https://doi.org/10.1152/ajplung.00198.2023
  12. Biochim Biophys Acta Mol Cell Res. 2023 Dec 11. pii: S0167-4889(23)00221-5. [Epub ahead of print] 119648
    The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
    Xiao-Long Su, Zhi-Ren Su, Wei-Hua Xu.
      Diapause is a widespread adaptation of insects that enables them to survive during unfavorable seasons and is characterized by suppressed metabolism and increased lifespan. Previous works have demonstrated that high levels of reactive oxygen species (ROS) and hypoxia-inducible factor-1α (HIF-1α) in the pupal brain of the moth Helicoverpa armigera induce diapause and extend lifespan by downregulating mitochondrial transcription factor A (TFAM). However, the molecular mechanisms of ROS-HIF-1α regulating metabolic activity to extend lifespan are still poorly understood. Here, we show that the mitochondrial abundance in diapause-type pupal brains is markedly lower than that in their nondiapause-type pupae, suggesting that ROS-HIF-1α signaling negatively regulates the number of mitochondria. The protease Lon, a major mitochondrial matrix protease, can respond to ROS signals. It is activated by transcription factor HIF-1α, which specifically binds the LON promoter to promote its expression. A high level of LON mediates the degradation of TFAM, which is a crucial factor in regulating mitochondrial abundance and metabolic activity. We believe this is the first report that a previously unrecognized regulatory pathway, ROS-HIF-1α-LON-TFAM, reduces mitochondrial activity to induce diapause, extending insect lifespan.
    Keywords:  Diapause; HIF-1α; LON; ROS; TFAM
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119648
  13. Mitochondrion. 2023 Dec 11. pii: S1567-7249(23)00105-8. [Epub ahead of print] 101825
    CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
    Rajdeep Das, Sebabrata Maity, Palamou Das, Izaz Monir Kamal, Saikat Chakrabarti, Oishee Chakrabarti.
      Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.
    DOI:  https://doi.org/10.1016/j.mito.2023.101825
  14. FASEB J. 2024 Jan;38(1): e23343
    Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
    Logan R Timmins, Milene Ortiz-Silva, Bharat Joshi, Y Lydia Li, Fiona H Dickson, Timothy H Wong, Kurt R Vandevoorde, Ivan R Nabi.
      Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA-MB-231 triple-negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non-phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho-associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA-MB-231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae-independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA-MB-231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1-ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild-type MDA-MB-231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK-dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy.
    Keywords:  AMPK; caveolin-1; mitochondria; mitophagy; reactive oxygen species; rho kinase
    DOI:  https://doi.org/10.1096/fj.202201872RR
  15. Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938
    The critical roles of STING in mitochondrial homeostasis.
    Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
    Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING
    DOI:  https://doi.org/10.1016/j.bcp.2023.115938
  16. J Appl Physiol (1985). 2023 Dec 14.
    The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
    Jenna C Wong, Ashley N Oliveira, Priyanka Khemraj, David A Hood.
      TFE3 is a transcription factor that activates the expression of lysosomal genes involved in the clearance of dysfunctional mitochondria, termed mitophagy. With exercise, TFE3 is presumed to optimize the mitochondrial pool through the removal of organelles via lysosomes. However, the molecular mechanisms of the involved pathways remain unknown. Wild-type (WT) and TFE3 knockout (KO) mice were subjected to 6 weeks of voluntary wheel running as an endurance training regimen. This was followed by a 45-minute bout of in situ stimulation of the sciatic nerve innervating hindlimb muscles to evaluate muscle fatigue and contractile properties. A subset of animals was treated with colchicine to measure autophagy and mitophagy flux. Fatigability during stimulation was reduced with training in WT animals, as seen by a 13% increase in percent of maximum force at 5 minutes of stimulation, and a 30% increase at 30 minutes. Permeabilized fiber oxygen consumption was also improved with training. Concurrent with improved muscle and mitochondrial function, COX activity and COX I protein expression were increased in trained WT animals compared to untrained animals, signifying an increase in mitochondrial content. These training adaptations were abolished with the loss of TFE3. Surprisingly, the absence of TFE3 did not affect lysosomal content, nor did it blunt the induction of mitophagy flux with contractile activity compared to WT mice. Our results suggest that the loss of TFE3 compromises beneficial training adaptations that lead to improved muscle endurance and mitochondrial function.
    Keywords:  TFE3; exercise; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00484.2023
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