bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒01‒08
seventeen papers selected by
Avinash N. Mukkala, University of Toronto
  1. Inner mitochondrial membrane protein Prohibitin 1 mediates Nix-induced, Parkin-independent mitophagy.
  2. Monitoring mitochondrial translation by pulse SILAC.
  3. Human mitochondria require mtRF1 for translation termination at non-canonical stop codons.
  4. The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
  5. An Updated Review of Mitochondrial Transplantation as a Potential Therapeutic Strategy Against Cerebral Ischemia and Cerebral Ischemia/Reperfusion Injury.
  6. The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy.
  7. Metabolic regulation of the proteasome under hypoxia by Poldip2 controls fibrotic signaling in vascular smooth muscle cells.
  8. Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle.
  9. Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.
  10. The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
  11. Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
  12. TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.
  13. Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.
  14. MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.
  15. Lactate metabolism is essential in early-onset mitochondrial myopathy.
  16. ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.
  17. Metabolic regulation of species-specific developmental rates.
  1. Sci Rep. 2023 Jan 02. 13(1): 18
    Inner mitochondrial membrane protein Prohibitin 1 mediates Nix-induced, Parkin-independent mitophagy.
    Kibrom M Alula, Yaritza Delgado-Deida, Rosemary Callahan, Andreas Till, Lucia Underwood, Winston E Thompson, Rhonda F Souza, Themistocles Dassopoulos, Joseph Onyiah, K Venuprasad, Arianne L Theiss.
      Autophagy of damaged mitochondria, called mitophagy, is an important organelle quality control process involved in the pathogenesis of inflammation, cancer, aging, and age-associated diseases. Many of these disorders are associated with altered expression of the inner mitochondrial membrane (IMM) protein Prohibitin 1. The mechanisms whereby dysfunction occurring internally at the IMM and matrix activate events at the outer mitochondrial membrane (OMM) to induce mitophagy are not fully elucidated. Using the gastrointestinal epithelium as a model system highly susceptible to autophagy inhibition, we reveal a specific role of Prohibitin-induced mitophagy in maintaining intestinal homeostasis. We demonstrate that Prohibitin 1 induces mitophagy in response to increased mitochondrial reactive oxygen species (ROS) through binding to mitophagy receptor Nix/Bnip3L and independently of Parkin. Prohibitin 1 is required for ROS-induced Nix localization to mitochondria and maintaining homeostasis of epithelial cells highly susceptible to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41598-022-26775-x
  2. J Biol Chem. 2023 Jan 02. pii: S0021-9258(22)01308-4. [Epub ahead of print] 102865
    Monitoring mitochondrial translation by pulse SILAC.
    Koshi Imami, Matthias Selbach, Yasushi Ishihama.
      Mitochondrial ribosomes are specialized to translate the 13 membrane proteins encoded in the mitochondrial genome, which shapes the oxidative phosphorylation (OXPHOS) complexes essential for cellular energy metabolism. Despite the importance of mitochondrial translation control, it is challenging to identify and quantify the mitochondrial-encoded proteins due to their hydrophobic nature and low abundance. Here, we introduce a mass spectrometry-based proteomic method that combines biochemical isolation of mitochondria with pulse stable isotope labeling by amino acids in cell culture (pSILAC). Our method provides the highest protein identification rate with the shortest measurement time among currently available methods, enabling us to quantify 12 out of the 13 mitochondrial-encoded proteins. We applied this method to uncover the global picture of (post-)translational regulation of both mitochondrial- and nuclear-encoded subunits of OXPHOS complexes. We found that inhibition of mitochondrial translation led to degradation of orphan nuclear-encoded subunits that are considered to form subcomplexes with the mitochondrial-encoded subunits. This method should be readily applicable to study mitochondrial translation programs in many contexts, including oxidative stress and mitochondrial disease.
    Keywords:  Mitochondria; OXPHOS; Protein complex; Proteomics; Translation; pulse SILAC
    DOI:  https://doi.org/10.1016/j.jbc.2022.102865
  3. Nat Commun. 2023 Jan 03. 14(1): 30
    Human mitochondria require mtRF1 for translation termination at non-canonical stop codons.
    Annika Krüger, Cristina Remes, Dmitrii Igorevich Shiriaev, Yong Liu, Henrik Spåhr, Rolf Wibom, Ilian Atanassov, Minh Duc Nguyen, Barry S Cooperman, Joanna Rorbach.
      The mitochondrial translation machinery highly diverged from its bacterial counterpart. This includes deviation from the universal genetic code, with AGA and AGG codons lacking cognate tRNAs in human mitochondria. The locations of these codons at the end of COX1 and ND6 open reading frames, respectively, suggest they might function as stop codons. However, while the canonical stop codons UAA and UAG are known to be recognized by mtRF1a, the release mechanism at AGA and AGG codons remains a debated issue. Here, we show that upon the loss of another member of the mitochondrial release factor family, mtRF1, mitoribosomes accumulate specifically at AGA and AGG codons. Stalling of mitoribosomes alters COX1 transcript and protein levels, but not ND6 synthesis. In addition, using an in vitro reconstituted mitochondrial translation system, we demonstrate the specific peptide release activity of mtRF1 at the AGA and AGG codons. Together, our results reveal the role of mtRF1 in translation termination at non-canonical stop codons in mitochondria.
    DOI:  https://doi.org/10.1038/s41467-022-35684-6
  4. Nat Commun. 2023 Jan 03. 14(1): 39
    The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
    Jiyao Song, Liesa Steidle, Isabelle Steymans, Jasjot Singh, Anne Sanner, Lena Böttinger, Dominic Winter, Thomas Becker.
      The mitochondrial F1FO-ATP synthase produces the bulk of cellular ATP. The soluble F1 domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to the membrane embedded rotor of the FO domain. The assembly of the F1 domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F1 domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F1FO-ATP synthase.
    DOI:  https://doi.org/10.1038/s41467-022-35720-5
  5. Mol Neurobiol. 2023 Jan 03.
    An Updated Review of Mitochondrial Transplantation as a Potential Therapeutic Strategy Against Cerebral Ischemia and Cerebral Ischemia/Reperfusion Injury.
    Huatuo Huang, Thura Tun Oo, Nattayaporn Apaijai, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Regardless of the progress made in the pathogenesis of ischemic stroke, it remains a leading cause of adult disability and death. To date, the most effective treatment for ischemic stroke is the timely recanalization of the occluded artery. However, the short time window and reperfusion injury have greatly limited its application and efficacy. Mitochondrial dysfunction and ATP depletion have become regarded as being hallmarks of neuropathophysiology following ischemic stroke. Mitochondrial transplantation is a novel potential therapeutic intervention for ischemic stroke that has sparked widespread concern during the past few years. This review summarizes and discusses the effects of mitochondrial transplantation in in vitro and in vivo ischemic stroke models. In addition, pharmacological interventions promoting mitochondrial transplantation are reviewed and discussed. We also discuss the potential challenges to the clinical application of mitochondrial transplantation in the treatment of ischemic stroke.
    Keywords:  Brain; Cerebral ischemia; Cerebral ischemia/reperfusion; Ischemic stroke; Mitochondrial transfer; Mitochondrial transplantation
    DOI:  https://doi.org/10.1007/s12035-022-03200-y
  6. Autophagy. 2023 Jan 01. 1-18
    The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy.
    Bo Zhang, Shuai Xu, Minxuan Liu, Yanli Wei, Qian Wang, Wentao Shen, Cao-Qi Lei, Qiyun Zhu.
      Mitophagy is a form of autophagy that plays a key role in maintaining the homeostasis of functional mitochondria in the cell. Viruses have evolved various strategies to manipulate mitophagy to escape host immune responses and promote virus replication. In this study, the nucleoprotein (NP) of H1N1 virus (PR8 strain) was identified as a regulator of mitophagy. We revealed that NP-mediated mitophagy leads to the degradation of the mitochondria-anchored protein MAVS, thereby blocking MAVS-mediated antiviral signaling and promoting virus replication. The NP-mediated mitophagy is dependent on the interaction of NP with MAVS and the cargo receptor TOLLIP. Moreover, Y313 of NP is a key residue for the MAVS-NP interaction and NP-mediated mitophagy. The NPY313F mutation significantly attenuates the virus-induced mitophagy and the virus replication in vitro and in vivo. Taken together, our findings uncover a novel mechanism by which the NP of influenza virus induces mitophagy to attenuate innate immunity.Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; ATG12: autophagy related 12; CCCP: carbonyl cyanide 3-chlorophenyl hydrazone; co-IP: co-immunoprecipitation; COX4/COXIV: cytochrome c oxidase subunit 4; DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride; EID50: 50% egg infective dose; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; hpi: hours post-infection; IAV: influenza A virus; IFN: interferon; IP: immunoprecipitation; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MLD50: 50% mouse lethal dose; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NP: nucleoprotein; PB1: basic polymerase 1; RFP: red fluorescent protein; RIGI: RNA sensor RIG-I; RIGI-N: RIGI-CARD; SeV: Sendai virus; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOLLIP: toll interacting protein; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; Vec: empty vector; vRNP: viral ribonucleoprotein.
    Keywords:  Influenza A virus; MAVS; TOLLIP; mitophagy; nucleoprotein
    DOI:  https://doi.org/10.1080/15548627.2022.2162798
  7. Free Radic Biol Med. 2022 Dec 31. pii: S0891-5849(22)01132-7. [Epub ahead of print]
    Metabolic regulation of the proteasome under hypoxia by Poldip2 controls fibrotic signaling in vascular smooth muscle cells.
    Felipe Paredes, Holly C Williams, Izabela Suster, Macarena Tejos, Roberto Fuentealba, Bethany Bogan, Claire M Holden, Alejandra San Martin.
      The polymerase delta interacting protein 2 (Poldip2) is a nuclear-encoded mitochondrial protein required for oxidative metabolism. Under hypoxia, Poldip2 expression is repressed by an unknown mechanism. Therefore, low levels of Poldip2 are required to maintain glycolytic metabolism. The Cellular Communication Network Factor 2 (CCN2, Connective tissue growth factor, CTGF) is a profibrogenic molecule highly expressed in cancer and vascular inflammation in advanced atherosclerosis. Because CCN2 is upregulated under hypoxia and is associated with glycolytic metabolism, we hypothesize that Poldip2 downregulation is responsible for the upregulation of profibrotic signaling under hypoxia. Here, we report that Poldip2 is repressed under hypoxia by a mechanism that requires the activation of the enhancer of zeste homolog 2 repressive complex (EZH2) downstream from the Cyclin-Dependent Kinase 2 (CDK2). Importantly, we found that Poldip2 repression is required for CCN2 expression downstream of metabolic inhibition of the ubiquitin-proteasome system (UPS)-dependent stabilization of the serum response factor. Pharmacological or gene expression inhibition of CDK2 under hypoxia reverses Poldip2 downregulation, the inhibition of the UPS, and the expression of CCN2, collagen, and fibronectin. Thus, our findings connect cell cycle regulation and proteasome activity to mitochondrial function and fibrotic responses under hypoxia.
    Keywords:  CCN2; Cell cycle; Hypoxia; Mitochondria; Poldip2; Proteasome
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.098
  8. J Cachexia Sarcopenia Muscle. 2023 Jan 05.
    Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle.
    Stephen E Alway, Hector G Paez, Christopher R Pitzer, Peter J Ferrandi, Mohammad Moshahid Khan, Junaith S Mohamed, James A Carson, Michael R Deschenes.
      BACKGROUND: Injection of exogenous mitochondria has been shown to improve the ischaemia-damaged myocardium, but the effect of mitochondrial transplant therapy (MTT) to restore skeletal muscle mass and function has not been tested following neuromuscular injury. Therefore, we tested the hypothesis that MTT would improve the restoration of muscle function after injury.METHODS: BaCl2 was injected into the gastrocnemius muscle of one limb of 8-12-week-old C57BL/6 mice to induce damage without injury to the resident stem cells. The contralateral gastrocnemius muscle was injected with phosphate-buffered saline (PBS) and served as the non-injured intra-animal control. Mitochondria were isolated from donor mice. Donor mitochondria were suspended in PBS or PBS without mitochondria (sham treatment) and injected into the tail vein of BaCl2 injured mice 24 h after the initial injury. Muscle repair was examined 7, 14 and 21 days after injury.
    RESULTS: MTT did not increase systemic inflammation in mice. Muscle mass 7 days following injury was 21.9 ± 2.1% and 17.4 ± 1.9% lower (P < 0.05) in injured as compared with non-injured intra-animal control muscles in phosphate-buffered saline (PBS)- and MTT-treated animals, respectively. Maximal plantar flexor muscle force was significantly lower in injured as compared with uninjured muscles of PBS-treated (-43.4 ± 4.2%, P < 0.05) and MTT-treated mice (-47.7 ± 7.3%, P < 0.05), but the reduction in force was not different between the experimental groups. The percentage of collagen and other non-contractile tissue in histological muscle cross sections, was significantly greater in injured muscles of PBS-treated mice (33.2 ± 0.2%) compared with MTT-treated mice (26.5 ± 0.2%) 7 days after injury. Muscle wet weight and maximal muscle force from injured MTT-treated mice had recovered to control levels by 14 days after the injury. However, muscle mass and force had not improved in PBS-treated animals by 14 days after injury. The non-contractile composition of the gastrocnemius muscle tissue cross sections was not different between control, repaired PBS-treated and repaired MTT-treated mice 14 days after injury. By 21 days following injury, PBS-treated mice had fully restored gastrocnemius muscle mass of the injured muscle to that of the uninjured muscle, although maximal plantar flexion force was still 19.4 ± 3.7% (P < 0.05) lower in injured/repaired gastrocnemius as compared with uninjured intra-animal control muscles.
    CONCLUSIONS: Our results suggest that systemic mitochondria delivery can enhance the rate of muscle regeneration and restoration of muscle function following injury.
    Keywords:  Mitochondria; Muscle fibre types; Muscle force; Muscle injury; Regeneration
    DOI:  https://doi.org/10.1002/jcsm.13153
  9. Cell Mol Immunol. 2023 Jan 04.
    Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.
    Chia George Hsu, Wenjia Li, Mark Sowden, Camila Lage Chávez, Bradford C Berk.
      Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in a mouse sepsis model. Using cultured peritoneal and bone marrow-derived macrophages, we demonstrated that Pnpt1 regulated NLRP3 inflammasome-dependent IL-1β release in response to lipopolysaccharide (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS administration and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein (MAVS) but not NF-κB signaling. Collectively, these data suggest that Pnpt1 is an important mediator of inflammation, as shown by activation of the NLRP3 inflammasome in murine sepsis and cultured macrophages.
    Keywords:  Inflammasome; Macrophage; Mitochondria; Pnpt1
    DOI:  https://doi.org/10.1038/s41423-022-00962-2
  10. Cell Rep. 2022 Dec 23. pii: S2211-1247(22)01798-3. [Epub ahead of print] 111899
    The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
    Arthur Bassot, Junsheng Chen, Kei Takahashi-Yamashiro, Megan C Yap, Christine Silvia Gibhardt, Giang N T Le, Saaya Hario, Yusuke Nasu, Jack Moore, Tomas Gutiérrez, Lucas Mina, Heather Mast, Audric Moses, Rakesh Bhat, Klaus Ballanyi, Hélène Lemieux, Roberto Sitia, Ester Zito, Ivan Bogeski, Robert E Campbell, Thomas Simmen.
      Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
    Keywords:  CP: Metabolism; CP: Molecular biology; ER; ER stress; ERO1; MAMs; MERCs; PERK; bioenergetics; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; mitochondria-endoplasmic reticulum contacts; oxidoreductase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111899
  11. J Biol Chem. 2023 Jan 02. pii: S0021-9258(22)01306-0. [Epub ahead of print] 102863
    Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
    Elizabeth J Osterlund, Nehad Hirmiz, Dang Nguyen, James M Pemberton, Qiyin Fang, David W Andrews.
      The pro-apoptotic BH3-only endoplasmic reticulum (ER) resident protein BIK, positively regulates mitochondrial outer membrane permeabilization (MOMP), the point-of-no-return in apoptosis. It is generally accepted that BIK functions at a distance from mitochondria by binding and sequestering anti-apoptotic proteins at the ER thereby promoting ER calcium release. Although BIK is predominantly localized to the ER, we detect by FLIM-FRET microscopy, BH3 region-dependent direct binding between BIK and mitochondria-localized chimeric mutants of the anti-apoptotic proteins BCL-XL and BCL-2 in both BMK and MCF-7 cells. Direct binding was accompanied by cell-type specific differential relocalization in response to co-expression of either BIK or one of its target binding partners, BCL-XL, when co-expressed in cells. In BMK cells with genetic deletion of both BAX and BAK (BMK-DKO) our data suggest a fraction of BIK protein moves towards mitochondria in response to the expression of a mitochondria-localized BCL-XL mutant. In contrast, in MCF-7 cells our data suggest BIK is localized at both ER and mitochondria-associated endoplasmic reticulum membranes (MAMs) and binds to the mitochondria-localized BCL-XL mutant via relocalization of BCL-XL to ER and MAMs. Rather than functioning at a distance, our data suggest BIK initiates MOMP via direct interactions with ER and mitochondria-localized anti-apoptotic proteins, that occur via ER-mitochondria contact sites, and/or by relocalization of either BIK or anti-apoptotic proteins in cells.
    Keywords:  BCL-2 family; BCL-2 interacting killer; BIK; FLIM-FRET; apoptosis; subcellular localization fluorescence lifetime imaging microscopy
    DOI:  https://doi.org/10.1016/j.jbc.2022.102863
  12. Metabolism. 2023 Jan 02. pii: S0026-0495(22)00261-X. [Epub ahead of print] 155383
    TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.
    Hao Zhou, Zhe Dai, Jialei Li, Jin Wang, Hang Zhu, Xing Chang, Yijin Wang.
      BACKGROUND: The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca2+ leak activity that modulates cellular responses to various cellular stressors.METHODS: In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) mice.
    RESULTS: Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6CKO mice, and largely absent in TMBIM6TG mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca2+ uptake.
    CONCLUSION: We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM.
    Keywords:  Mitochondria; Septic cardiomyopathy; TMBIM6; VDAC1
    DOI:  https://doi.org/10.1016/j.metabol.2022.155383
  13. Proc Natl Acad Sci U S A. 2023 Jan 10. 120(2): e2204750120
    Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.
    Juliane Cruz Campos, Luiz Henrique Marchesi Bozi, Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque, Annika Traa, Takafumi Ogawa, Alexander M van der Bliek, Afshin Beheshti, Edward T Chouchani, Jeremy M Van Raamsdonk, T Keith Blackwell, Julio Cesar Batista Ferreira.
      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 Caenorhabditis elegans. 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 (isp-1,nuo-6, daf-2, eat-2, and CA-AAK-2), 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.
    Keywords:  C. elegans; aging; exercise; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1073/pnas.2204750120
  14. EMBO Rep. 2023 Jan 02. e55643
    MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.
    Shashi Anand, Mohammad Aslam Khan, Haseeb Zubair, Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Sachin Kumar Deshmukh, Shafquat Azim, Sanjeev Kumar Srivastava, Seema Singh, Ajay Pratap Singh.
      Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.
    Keywords:  HIF1α; MYB; hypoxia; metabolic reprogramming; pancreatic cancer
    DOI:  https://doi.org/10.15252/embr.202255643
  15. Sci Adv. 2023 Jan 04. 9(1): eadd3216
    Lactate metabolism is essential in early-onset mitochondrial myopathy.
    Zhenkang Chen, Bogdan Bordieanu, Rushendhiran Kesavan, Nicholas P Lesner, Siva Sai Krishna Venigalla, Spencer D Shelton, Ralph J DeBerardinis, Prashant Mishra.
      Myopathies secondary to mitochondrial electron transport chain (ETC) dysfunction can result in devastating disease. While the consequences of ETC defects have been extensively studied in culture, little in vivo data are available. Using a mouse model of severe, early-onset mitochondrial myopathy, we characterized the proteomic, transcriptomic, and metabolic characteristics of disease progression. Unexpectedly, ETC dysfunction in muscle results in reduced expression of glycolytic enzymes in our animal model and patient muscle biopsies. The decrease in glycolysis was mediated by loss of constitutive Hif1α signaling, down-regulation of the purine nucleotide cycle enzyme AMPD1, and activation of AMPK. In vivo isotope tracing experiments indicated that myopathic muscle relies on lactate import to supply central carbon metabolites. Inhibition of lactate import reduced steady-state levels of tricarboxylic acid cycle intermediates and compromised the life span of myopathic mice. These data indicate an unexpected mode of metabolic reprogramming in severe mitochondrial myopathy that regulates disease progression.
    DOI:  https://doi.org/10.1126/sciadv.add3216
  16. Free Radic Biol Med. 2022 Dec 30. pii: S0891-5849(22)01131-5. [Epub ahead of print]195 219-230
    ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.
    Xin Tan, Yong-Feng Chen, Shi-Ying Zou, Wei-Jie Wang, Ning-Ning Zhang, Zheng-Yu Sun, Wei Xian, Xiao-Rong Li, Bi Tang, Hong-Ju Wang, Qin Gao, Pin-Fang Kang.
      The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.
    Keywords:  Aldehyde dehydrogenase 2; Apoptosis; Mitochondrial fusion and fission; Mitochondrial permeability transition pore; PI3K/AKT/mTOR; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.097
  17. Nature. 2023 Jan 04.
    Metabolic regulation of species-specific developmental rates.
    Margarete Diaz-Cuadros, Teemu P Miettinen, Owen S Skinner, Dylan Sheedy, Carlos Manlio Díaz-García, Svetlana Gapon, Alexis Hubaud, Gary Yellen, Scott R Manalis, William M Oldham, Olivier Pourquié.
      Animals display substantial inter-species variation in the rate of embryonic development despite a broad conservation of the overall sequence of developmental events. Differences in biochemical reaction rates, including the rates of protein production and degradation, are thought to be responsible for species-specific rates of development1-3. However, the cause of differential biochemical reaction rates between species remains unknown. Here, using pluripotent stem cells, we have established an in vitro system that recapitulates the twofold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we show that mass-specific metabolic rates scale with the developmental rate and are therefore higher in mouse cells than in human cells. Reducing these metabolic rates by inhibiting the electron transport chain slowed down the segmentation clock by impairing the cellular NAD+/NADH redox balance and, further downstream, lowering the global rate of protein synthesis. Conversely, increasing the NAD+/NADH ratio in human cells by overexpression of the Lactobacillus brevis NADH oxidase LbNOX increased the translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including accelerating the differentiation of human pluripotent stem cells for disease modelling and cell-based therapies.
    DOI:  https://doi.org/10.1038/s41586-022-05574-4
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