bims-mitdyn 2023-10-29 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2023‒10‒29
nine papers selected by
Edmond Chan, Queen’s University, School of Medicine

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
Lactate activates the mitochondrial electron transport chain independently of its metabolism.
Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.
Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.
Mitochondrial gene expression is required for platelet function and blood clotting.
Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.
Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.
Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.
Reducing mitochondrial mysteries.

Nat Commun. 2023 Oct 23. 14(1): 6721

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.

Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

DOI: https://doi.org/10.1038/s41467-023-42564-0
Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]

Lactate activates the mitochondrial electron transport chain independently of its metabolism.

Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.

  Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
Proc Natl Acad Sci U S A. 2023 Oct 31. 120(44): e2313010120

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Yvette C Wong, Nirupa D Jayaraj, Tayler B Belton, George C Shum, Hannah E Ball, Dongjun Ren, Abigail L D Tadenev, Dimitri Krainc, Robert W Burgess, Daniela M Menichella.

  Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Keywords:  Charcot–Marie–Tooth disease; inter-organelle contact site; lysosome; mitochondria; peripheral neuropathy

DOI:  https://doi.org/10.1073/pnas.2313010120
Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00336-7. [Epub ahead of print]

Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.

Alexia Pearah, Balamurugan Ramatchandirin, Ting Liu, Risa M Wolf, Arisa Ikeda, Sally Radovick, Hiromi Sesaki, Fredric E Wondisford, Brian O'Rourke, Ling He.

  Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.

Keywords:  AKT; AMPK targeting peptides; AMPKαS496 phosphorylation; PKA; hyperglycemia; liver gluconeogenesis; mitochondrial fission

DOI:  https://doi.org/10.1016/j.chembiol.2023.09.017
Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01324-4. [Epub ahead of print]42(11): 113312

Mitochondrial gene expression is required for platelet function and blood clotting.

Tara R Richman, Judith A Ermer, Jessica Baker, Stefan J Siira, Benjamin T Kile, Matthew D Linden, Oliver Rackham, Aleksandra Filipovska.

  Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.

Keywords:  CP: Immunology; megakaryocytes; mitochondria; mitochondrial gene expression; platelets; translation

DOI:  https://doi.org/10.1016/j.celrep.2023.113312
FASEB J. 2023 11;37(11): e23265

Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.

Qianqian Yang, Lulu Wang, Yuehong Liang, Qingyu He, Qi Sun, Jing Luo, Hongdi Cao, Yi Fang, Yang Zhou, Junwei Yang, Ping Wen, Lei Jiang.

  Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

Keywords:  OMA1; OPA1; UCP2; mitochondria; podocyte injury

DOI:  https://doi.org/10.1096/fj.202301055R
J Biol Chem. 2023 Oct 20. pii: S0021-9258(23)02408-0. [Epub ahead of print] 105380

Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.

Kelsey A Nolden, Megan C Harwig, R Blake Hill.

  Mitochondrial Fission Protein 1 (Fis1) and Dynamin Related Protein 1 (Drp1) are the only two proteins evolutionarily conserved for mitochondrial fission, and directly interact in S. cerevisiae to facilitate membrane scission. However, it remains unclear if a direct interaction is conserved in higher eukaryotes as other Drp1 recruiters, not present in yeast, are known. Using NMR, differential scanning fluorimetry, and microscale thermophoresis, we determined that human Fis1 directly interacts with human Drp1 (KD = 12-68 μM), and appears to prevent Drp1 assembly, but not GTP hydrolysis. Similar to yeast, the Fis1-Drp1 interaction appears governed by two structural features of Fis1: its N-terminal arm and a conserved surface. Alanine scanning mutagenesis of the arm identified both loss- and gain-of-function alleles with mitochondrial morphologies ranging from highly elongated (N6A) to highly fragmented (E7A) demonstrating a profound ability of Fis1 to govern morphology in human cells. An integrated analysis identified a conserved Fis1 residue, Y76, that upon substitution to alanine, but not phenylalanine, also caused highly fragmented mitochondria. The similar phenotypic effects of the E7A and Y76A substitutions, along with NMR data, support that intramolecular interactions occur between the arm and a conserved surface on Fis1 to promote Drp1-mediated fission as in S. cerevisiae. These findings indicate that some aspects of Drp1-mediated fission in humans derive from direct Fis1-Drp1 interactions that are conserved across eukaryotes.

Keywords:  biophysics; cell biology; confocal microscopy; fission; microscale thermophoresis (MST); mitochondria; mitochondrial dynamics; nuclear magnetic resonance (NMR); protein-protein interaction

DOI:  https://doi.org/10.1016/j.jbc.2023.105380
Autophagy. 2023 Oct 24.

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.

Kun Gao, Yingji Chen, Ren Mo, Chenji Wang.

  Mitophagy, the process of removing damaged mitochondria to promote cell survival, plays a crucial role in cellular functionality. However, excessive, or uncontrolled mitophagy can lead to reduced mitochondrial content that burdens the remaining organelles, triggering mitophagy-mediated cell death. FBXL4 mutations, which affect the substrate-binding adaptor of the CUL1 (cullin 1)-RING ubiquitin ligase complex (CRL1), have been linked to mitochondrial DNA depletion syndrome type 13 (MTDPS13) characterized by reduced mtDNA content and impaired energy production in affected organs. However, the mechanism behind FBXL4 mutation-driven MTDPS13 remain poorly understood. In a recent study, we demonstrate that the CRL1-FBXL4 complex promotes the degradation of BNIP3 and BNIP3L, two key mitophagy cargo receptors. Deficiency of FBXL4 results in a strong accumulation of BNIP3 and BNIP3L proteins and triggers high levels of BNIP3- and BNIP3L-dependent mitophagy. Patient-derived FBXL4 mutations do not affect its interaction with BNIP3 and BNIP3L but impair the assembly of an active CRL1-FBXL4 complex. Furthermore, excessive mitophagy is observed in knockin mice carrying a patient-derived FBXL4 mutation, and in cortical neurons generated from human patient induced pluripotent stem cells (hiPSCs). These findings support the model that the CRL1-FBXL4 complex tightly restricts basal mitophagy, and its dysregulation leads to severe symptoms of MTDPS13.

Keywords:  Lysosome; mitochondria; mitophagy; multi-system disorder; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2023.2274260
Nat Chem Biol. 2023 Oct 26.

Reducing mitochondrial mysteries.

Rachel M Guerra, David J Pagliarini.

DOI: https://doi.org/10.1038/s41589-023-01435-x