bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021–07–18
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease.
  2. Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development.
  3. Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development.
  4. Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery.
  5. Long-lived mitochondrial cristae proteins in mouse heart and brain.
  6. NMR identification of a conserved Drp1 cardiolipin-binding motif essential for stress-induced mitochondrial fission.
  7. ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
  8. Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
  9. Loss of UCHL1 rescues the defects related to Parkinson's disease by suppressing glycolysis.
  10. Mechanometabolism: Mitochondria promote resilience under pressure.
  11. Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
  12. Mitochondrial compartmentalization: emerging themes in structure and function.
  1. Cell Metab. 2021 Jul 08. pii: S1550-4131(21)00283-7. [Epub ahead of print]
    Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease.
    Shanshan Liu, Song Fu, Guodong Wang, Yu Cao, Lanlan Li, Xuemei Li, Jun Yang, Ning Li, Yabing Shan, Yang Cao, Yan Ma, Mengqiu Dong, Qinghua Liu, Hui Jiang.
      Electron transport chain (ETC) dysfunction or hypoxia causes toxic NADH accumulation. How cells regenerate NAD+ under such conditions remains elusive. Here, integrating bioinformatic analysis and experimental validation, we identify glycerol-3-phosphate (Gro3P) biosynthesis as an endogenous NAD+-regeneration pathway. Under genetic or pharmacological ETC inhibition, disrupting Gro3P synthesis inhibits yeast proliferation, shortens lifespan of C. elegans, impairs growth of cancer cells in culture and in xenografts, and causes metabolic derangements in mouse liver. Moreover, the Gro3P shuttle selectively regenerates cytosolic NAD+ under mitochondrial complex I inhibition; enhancing Gro3P synthesis promotes shuttle activity to restore proliferation of complex I-impaired cells. Mouse brain has much lower levels of Gro3P synthesis enzymes as compared with other organs. Strikingly, enhancing Gro3P synthesis suppresses neuroinflammation and extends lifespan in the Ndufs4-/- mice. Collectively, our results reveal Gro3P biosynthesis as an evolutionarily conserved coordinator of NADH/NAD+ redox homeostasis and present a therapeutic target for mitochondrial complex I diseases.
    Keywords:  ETC dysfunction and hypoxia; NAD(+) regeneration; glycerol-3-phosphate biosynthesis; mitochondrial complex I disease
    DOI:  https://doi.org/10.1016/j.cmet.2021.06.013
  2. Nat Metab. 2021 Jul 12.
    Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development.
    Ana Lima, Gabriele Lubatti, Jörg Burgstaller, Di Hu, Alistair P Green, Aida Di Gregorio, Tamzin Zawadzki, Barbara Pernaute, Elmir Mahammadov, Salvador Perez-Montero, Marian Dore, Juan Miguel Sanchez, Sarah Bowling, Margarida Sancho, Thomas Kolbe, Mohammad M Karimi, David Carling, Nick Jones, Shankar Srinivas, Antonio Scialdone, Tristan A Rodriguez.
      Cell competition is emerging as a quality-control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated before gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single-cell transcriptional profiling of eliminated mouse epiblast cells, we identify hallmarks of cell competition and mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. Moreover, we show that in the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequences can induce cell competition. Our results suggest that cell competition is a purifying selection that optimizes mitochondrial performance before gastrulation.
    DOI:  https://doi.org/10.1038/s42255-021-00422-7
  3. Nat Commun. 2021 Jul 16. 12(1): 4371
    Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development.
    Jianli He, Xun Shangguan, Wei Zhou, Ying Cao, Quan Zheng, Jun Tu, Gaolei Hu, Zi Liang, Cen Jiang, Liufu Deng, Shengdian Wang, Wen Yang, Yong Zuo, Jiao Ma, Rong Cai, Yalan Chen, Qiuju Fan, Baijun Dong, Wei Xue, Hongsheng Tan, Yitao Qi, Jianmin Gu, Bing Su, Y Eugene Chin, Guoqiang Chen, Qi Wang, Tianshi Wang, Jinke Cheng.
      Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.
    DOI:  https://doi.org/10.1038/s41467-021-24619-2
  4. Nat Commun. 2021 07 13. 12(1): 4284
    Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery.
    Corvin Walter, Adinarayana Marada, Tamara Suhm, Ralf Ernsberger, Vera Muders, Cansu Kücükköse, Pablo Sánchez-Martín, Zehan Hu, Abhishek Aich, Stefan Loroch, Fiorella Andrea Solari, Daniel Poveda-Huertes, Alexandra Schwierzok, Henrike Pommerening, Stanka Matic, Jan Brix, Albert Sickmann, Claudine Kraft, Jörn Dengjel, Sven Dennerlein, Tilman Brummer, F-Nora Vögtle, Chris Meisinger.
      The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.
    DOI:  https://doi.org/10.1038/s41467-021-24426-9
  5. J Cell Biol. 2021 Sep 06. pii: e202005193. [Epub ahead of print]220(9):
    Long-lived mitochondrial cristae proteins in mouse heart and brain.
    Ewa Bomba-Warczak, Seby L Edassery, Timothy J Hark, Jeffrey N Savas.
      Long-lived proteins (LLPs) have recently emerged as vital components of intracellular structures whose function is coupled to long-term stability. Mitochondria are multifaceted organelles, and their function hinges on efficient proteome renewal and replacement. Here, using metabolic stable isotope labeling of mice combined with mass spectrometry (MS)-based proteomic analysis, we demonstrate remarkable longevity for a subset of the mitochondrial proteome. We discovered that mitochondrial LLPs (mt-LLPs) can persist for months in tissues harboring long-lived cells, such as brain and heart. Our analysis revealed enrichment of mt-LLPs within the inner mitochondrial membrane, specifically in the cristae subcompartment, and demonstrates that the mitochondrial proteome is not turned over in bulk. Pioneering cross-linking experiments revealed that mt-LLPs are spatially restricted and copreserved within protein OXPHOS complexes, with limited subunit exchange throughout their lifetimes. This study provides an explanation for the exceptional mitochondrial protein lifetimes and supports the concept that LLPs provide key structural stability to multiple large and dynamic intracellular structures.
    DOI:  https://doi.org/10.1083/jcb.202005193
  6. Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2023079118. [Epub ahead of print]118(29):
    NMR identification of a conserved Drp1 cardiolipin-binding motif essential for stress-induced mitochondrial fission.
    Mukesh Mahajan, Nikhil Bharambe, Yutong Shang, Bin Lu, Abhishek Mandal, Pooja Madan Mohan, Rihua Wang, Jennifer C Boatz, Juan Manuel Martinez Galvez, Anna V Shnyrova, Xin Qi, Matthias Buck, Patrick C A van der Wel, Rajesh Ramachandran.
      Mitochondria form tubular networks that undergo coordinated cycles of fission and fusion. Emerging evidence suggests that a direct yet unresolved interaction of the mechanoenzymatic GTPase dynamin-related protein 1 (Drp1) with mitochondrial outer membrane-localized cardiolipin (CL), externalized under stress conditions including mitophagy, catalyzes essential mitochondrial hyperfragmentation. Here, using a comprehensive set of structural, biophysical, and cell biological tools, we have uncovered a CL-binding motif (CBM) conserved between the Drp1 variable domain (VD) and the unrelated ADP/ATP carrier (AAC/ANT) that intercalates into the membrane core to effect specific CL interactions. CBM mutations that weaken VD-CL interactions manifestly impair Drp1-dependent fission under stress conditions and induce "donut" mitochondria formation. Importantly, VD membrane insertion and GTP-dependent conformational rearrangements mediate only transient CL nonbilayer topological forays and high local membrane constriction, indicating that Drp1-CL interactions alone are insufficient for fission. Our studies establish the structural and mechanistic bases of Drp1-CL interactions in stress-induced mitochondrial fission.
    Keywords:  NMR; cardiolipin; dynamin; intrinsically disordered; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2023079118
  7. Nat Cell Biol. 2021 Jul;23(7): 684-691
    ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
    Li-Sheng Zhang, Qing-Ping Xiong, Sonia Peña Perez, Chang Liu, Jiangbo Wei, Cassy Le, Linda Zhang, Bryan T Harada, Qing Dai, Xinran Feng, Ziyang Hao, Yuru Wang, Xueyang Dong, Lulu Hu, En-Duo Wang, Tao Pan, Arne Klungland, Ru-Juan Liu, Chuan He.
      Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism3, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N1-methyladenosine (m1A), N3-methylcytidine (m3C), N1-methylguanosine (m1G) and N2,N2-dimethylguanosine (m22G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m22G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA4-6. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mitochondrial RNAs. Depletion of ALKBH7 leads to increased polycistronic mitochondrial RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, and notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity.
    DOI:  https://doi.org/10.1038/s41556-021-00709-7
  8. J Cell Sci. 2021 Jul 01. pii: jcs252197. [Epub ahead of print]134(13):
    Super-resolution microscopy reveals the arrangement of inner membrane protein complexes in mammalian mitochondria.
    Catherine S Palmer, Jieqiong Lou, Betty Kouskousis, Elvis Pandzic, Alexander J Anderson, Yilin Kang, Elizabeth Hinde, Diana Stojanovski.
      The mitochondrial inner membrane is a protein-rich environment containing large multimeric complexes, including complexes of the mitochondrial electron transport chain, mitochondrial translocases and quality control machineries. Although the inner membrane is highly proteinaceous, with 40-60% of all mitochondrial proteins localised to this compartment, little is known about the spatial distribution and organisation of complexes in this environment. We set out to survey the arrangement of inner membrane complexes using stochastic optical reconstruction microscopy (STORM). We reveal that subunits of the TIM23 complex, TIM23 and TIM44 (also known as TIMM23 and TIMM44, respectively), and the complex IV subunit COXIV, form organised clusters and show properties distinct from the outer membrane protein TOM20 (also known as TOMM20). Density based cluster analysis indicated a bimodal distribution of TIM44 that is distinct from TIM23, suggesting distinct TIM23 subcomplexes. COXIV is arranged in larger clusters that are disrupted upon disruption of complex IV assembly. Thus, STORM super-resolution microscopy is a powerful tool for examining the nanoscale distribution of mitochondrial inner membrane complexes, providing a 'visual' approach for obtaining pivotal information on how mitochondrial complexes exist in a cellular context.
    Keywords:  COXIV; Mitochondria; Mitochondrial complexes; Nanoscopy; Protein import; STORM; TIM23
    DOI:  https://doi.org/10.1242/jcs.252197
  9. Sci Adv. 2021 Jul;pii: eabg4574. [Epub ahead of print]7(28):
    Loss of UCHL1 rescues the defects related to Parkinson's disease by suppressing glycolysis.
    Su Jin Ham, Daewon Lee, Wen Jun Xu, Eunjoo Cho, Sekyu Choi, Soohong Min, Sunghyouk Park, Jongkyeong Chung.
      The role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1; also called PARK5) in the pathogenesis of Parkinson's disease (PD) has been controversial. Here, we find that the loss of UCHL1 destabilizes pyruvate kinase (PKM) and mitigates the PD-related phenotypes induced by PTEN-induced kinase 1 (PINK1) or Parkin loss-of-function mutations in Drosophila and mammalian cells. In UCHL1 knockout cells, cellular pyruvate production and ATP levels are diminished, and the activity of AMP-activated protein kinase (AMPK) is highly induced. Consequently, the activated AMPK promotes the mitophagy mediated by Unc-51-like kinase 1 (ULK1) and FUN14 domain-containing 1 (FUNDC1), which underlies the effects of UCHL1 deficiency in rescuing PD-related defects. Furthermore, we identify tripartite motif-containing 63 (TRIM63) as a previously unknown E3 ligase of PKM and demonstrate its antagonistic interaction with UCHL1 to regulate PD-related pathologies. These results suggest that UCHL1 is an integrative factor for connecting glycolysis and PD pathology.
    DOI:  https://doi.org/10.1126/sciadv.abg4574
  10. Curr Biol. 2021 Jul 12. pii: S0960-9822(21)00763-6. [Epub ahead of print]31(13): R859-R861
    Mechanometabolism: Mitochondria promote resilience under pressure.
    Thomas MacVicar, Thomas Langer.
      Mechanical forces regulate metabolism in healthy and cancerous tissue. A new study reveals that extracellular matrix stiffness modulates mitochondrial shape and function. The mechanical reprogramming of mitochondria confers resistance to oxidative stress and promotes survival.
    DOI:  https://doi.org/10.1016/j.cub.2021.05.065
  11. PLoS Biol. 2021 Jul;19(7): e3001302
    Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans.
    Maria Sladowska, Michał Turek, Min-Ji Kim, Krzysztof Drabikowski, Ben Hur Marins Mussulini, Karthik Mohanraj, Remigiusz A Serwa, Ulrike Topf, Agnieszka Chacinska.
      Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the "mitochondrial unfolded protein response" [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the "unfolded protein response activated by mistargeting of proteins" [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.
    DOI:  https://doi.org/10.1371/journal.pbio.3001302
  12. Trends Biochem Sci. 2021 Jul 06. pii: S0968-0004(21)00121-3. [Epub ahead of print]
    Mitochondrial compartmentalization: emerging themes in structure and function.
    Joseph C Iovine, Steven M Claypool, Nathan N Alder.
      Within cellular structures, compartmentalization is the concept of spatial segregation of macromolecules, metabolites, and biochemical pathways. Therefore, this concept bridges organellar structure and function. Mitochondria are morphologically complex, partitioned into several subcompartments by a topologically elaborate two-membrane system. They are also dynamically polymorphic, undergoing morphogenesis events with an extent and frequency that is only now being appreciated. Thus, mitochondrial compartmentalization is something that must be considered both spatially and temporally. Here, we review new developments in how mitochondrial structure is established and regulated, the factors that underpin the distribution of lipids and proteins, and how they spatially demarcate locations of myriad mitochondrial processes. Consistent with its pre-eminence, disturbed mitochondrial compartmentalization contributes to the dysfunction associated with heritable and aging-related diseases.
    Keywords:  bioenergetics; cristae; macromolecular trafficking; mitochondria; morphogenesis; ultrastructure
    DOI:  https://doi.org/10.1016/j.tibs.2021.06.003
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