bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒09‒04
eleven papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. The human mitochondrial genome contains a second light strand promoter.
  2. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
  3. Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
  4. Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
  5. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
  6. Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
  7. Structural insights into crista junction formation by the Mic60-Mic19 complex.
  8. Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
  9. Mitochondria in cancer: clean windmills or stressed tinkerers?
  10. Mitochondrial DNA is a major source of driver mutations in cancer.
  11. DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.
  1. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00764-X. [Epub ahead of print]
    The human mitochondrial genome contains a second light strand promoter.
    Benedict G Tan, Christian D Mutti, Yonghong Shi, Xie Xie, Xuefeng Zhu, Pedro Silva-Pinheiro, Katja E Menger, Héctor Díaz-Maldonado, Wei Wei, Thomas J Nicholls, Patrick F Chinnery, Michal Minczuk, Maria Falkenberg, Claes M Gustafsson.
      The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
    Keywords:  DdCBE; LSP2; POLRMT; light strand promoter; mitochondria; mitochondrial DNA; mitochondrial gene expression; mitochondrial promoter; mtDNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.011
  2. Nat Commun. 2022 Sep 02. 13(1): 5164
    Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
    Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl, Christian Münch.
      Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.
    DOI:  https://doi.org/10.1038/s41467-022-32564-x
  3. Nat Commun. 2022 Aug 30. 13(1): 5100
    Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNASer(GCU). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNASer(GCU) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNASer(GCU) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41467-022-32544-1
  4. J Cell Biol. 2022 Oct 03. pii: e202206140. [Epub ahead of print]221(10):
    Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
    Yvette C Wong, Soojin Kim, Jasmine Cisneros, Catherine G Molakal, Pingping Song, Steven J Lubbe, Dimitri Krainc.
      Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.
    DOI:  https://doi.org/10.1083/jcb.202206140
  5. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2117396119
    Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
    Na Ta, Chuanren Qu, Hao Wu, Di Zhang, Tiantian Sun, Yanjun Li, Jun Wang, Xiaohui Wang, Tieshan Tang, Quan Chen, Lei Liu.
      Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondrial glutathione transporter, to regulate mitoGSH levels. Specifically, knockdown of SLC25A11 in FUNDC2-knockout (KO) cells reduced mitoGSH and augmented erasin-induced ferroptosis. FUNDC2 also affected the stability of both SLC25A11 and glutathione peroxidase 4 (GPX4), key regulators for ferroptosis. Our results demonstrate that FUNDC2 modulates ferroptotic stress via regulating mitoGSH and further support a therapeutic strategy of cardioprotection by preventing mitoGSH depletion and ferroptosis.
    Keywords:  FUNDC2; SLC25A11; ferroptosis; mitoGSH; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2117396119
  6. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2206708119
    Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
    Lu Ren, Raghavender R Gopireddy, Guy Perkins, Hao Zhang, Valeriy Timofeyev, Yankun Lyu, Daphne A Diloretto, Pauline Trinh, Padmini Sirish, James L Overton, Wilson Xu, Nathan Grainger, Yang K Xiang, Elena N Dedkova, Xiao-Dong Zhang, Ebenezer N Yamoah, Manuel F Navedo, Phung N Thai, Nipavan Chiamvimonvat.
      The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.
    Keywords:  bradycardia; heart failure; mitochondria; sinoatrial node; sinoatrial node dysfunction
    DOI:  https://doi.org/10.1073/pnas.2206708119
  7. Sci Adv. 2022 Sep 02. 8(35): eabo4946
    Structural insights into crista junction formation by the Mic60-Mic19 complex.
    Tobias Bock-Bierbaum, Kathrin Funck, Florian Wollweber, Elisa Lisicki, Karina von der Malsburg, Alexander von der Malsburg, Janina Laborenz, Jeffrey K Noel, Manuel Hessenberger, Sibylle Jungbluth, Carola Bernert, Séverine Kunz, Dietmar Riedel, Hauke Lilie, Stefan Jakobs, Martin van der Laan, Oliver Daumke.
      Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie-shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function.
    DOI:  https://doi.org/10.1126/sciadv.abo4946
  8. Commun Biol. 2022 Sep 02. 5(1): 900
    Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
    Christopher J Groten, Brian A MacVicar.
      Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.
    DOI:  https://doi.org/10.1038/s42003-022-03848-1
  9. Trends Cell Biol. 2022 Aug 18. pii: S0962-8924(22)00191-X. [Epub ahead of print]
    Mitochondria in cancer: clean windmills or stressed tinkerers?
    Dario C Altieri.
      There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).
    Keywords:  Mic60; metabolism; metastasis; mitochondria; tumor plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.001
  10. Trends Cancer. 2022 Aug 27. pii: S2405-8033(22)00172-8. [Epub ahead of print]
    Mitochondrial DNA is a major source of driver mutations in cancer.
    Minsoo Kim, Mahnoor Mahmood, Ed Reznik, Payam A Gammage.
      Mitochondrial DNA (mtDNA) mutations are among the most common genetic events in all tumors and directly impact metabolic homeostasis. Despite the central role mitochondria play in energy metabolism and cellular physiology, the role of mutations in the mitochondrial genomes of tumors has been contentious. Until recently, genomic and functional studies of mtDNA variants were impeded by a lack of adequate tumor mtDNA sequencing data and available methods for mitochondrial genome engineering. These barriers and a conceptual fog surrounding the functional impact of mtDNA mutations in tumors have begun to lift, revealing a path to understanding the role of this essential metabolic genome in cancer initiation and progression. Here we discuss the history, recent developments, and challenges that remain for mitochondrial oncogenetics as the impact of a major new class of cancer-associated mutations is unveiled.
    Keywords:  cancer; genome editing; mitochondrial DNA; mutation selection
    DOI:  https://doi.org/10.1016/j.trecan.2022.08.001
  11. Brain. 2022 Aug 30. pii: awac313. [Epub ahead of print]
    DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.
    Dorien Imberechts, Inge Kinnart, Fieke Wauters, Joanne Terbeek, Liselot Manders, Keimpe Wierda, Kristel Eggermont, Rodrigo Furtado Madeiro, Carolyn Sue, Catherine Verfaillie, Wim Vandenberghe.
      Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson's disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson's disease, are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and iPSC-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization, but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and iPSC-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity with optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson's disease.
    Keywords:  DJ-1; Parkinson’s disease; autophagy; mitophagy; optineurin
    DOI:  https://doi.org/10.1093/brain/awac313
This page is being maintained by Thomas Krichel. It was last updated on 2022‒09‒06 at 17:08:53.