bims-mitdyn 2023-10-08 papers

Issue of 2023‒10‒08
six papers selected by
Edmond Chan, Queen’s University, School of Medicine

EMBO Rep. 2023 Oct 03. e56614

ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria.

Qing Zhou, Yuhao Yang, Zhanxue Xu, Kai Deng, Zhenzhen Zhang, Jiawei Hao, Ni Li, Yanling Wang, Ziwen Wang, Haihang Chen, Yang Yang, Fei Xiao, Xiaohong Zhang, Song Gao, Yi-Ping Li.

ATPase family AAA domain-containing protein 1 (ATAD1) maintains mitochondrial homeostasis by removing mislocalized tail-anchored (TA) proteins from the mitochondrial outer membrane (MOM). Hepatitis C virus (HCV) infection induces mitochondrial fragmentation, and viral NS5B protein is a TA protein. Here, we investigate whether ATAD1 plays a role in regulating HCV infection. We find that HCV infection has no effect on ATAD1 expression, but knockout of ATAD1 significantly enhances HCV infection; this enhancement is suppressed by ATAD1 complementation. NS5B partially localizes to mitochondria, dependent on its transmembrane domain (TMD), and induces mitochondrial fragmentation, which is further enhanced by ATAD1 knockout. ATAD1 interacts with NS5B, dependent on its three internal domains (TMD, pore-loop 1, and pore-loop 2), and induces the proteasomal degradation of NS5B. In addition, we provide evidence that ATAD1 augments the antiviral function of MAVS upon HCV infection. Taken together, we show that the mitochondrial quality control exerted by ATAD1 can be extended to a novel antiviral function through the extraction of the viral TA-protein NS5B from the mitochondrial outer membrane.

Keywords: hepatitis C virus infection; mitochondria; protein degradation; protein interaction; tail-anchored protein

DOI: https://doi.org/10.15252/embr.202256614

J Biol Chem. 2023 Sep 28. pii: S0021-9258(23)02331-1. [Epub ahead of print] 105303

A conserved, non-canonical insert in FIS1 mediates TBC1D15 and DRP1 recruitment for mitochondrial fission.

Ugochukwu K Ihenacho, Rafael Toro, Rana H Mansour, R Blake Hill.

Mitochondrial fission protein 1 (FIS1) is conserved in all eukaryotes, yet its function in metazoans is thought divergent from lower eukaryotes like fungi. To address this discrepancy, structure-based sequence alignments revealed a conserved but non-canonical three-residue insert (Ser-X-X) in a turn of FIS1, suggesting a conserved function. In vertebrate FIS1, this insert is serine (S45), lysine (K46), and tyrosine (Y47). To determine the biological role of the "SKY insert" in vertebrates, three variants were evaluated for their fold and tested in HCT116 cells for altered mitochondrial morphology and recruitment of effectors, DRP1 and TBC1D15. Substitution of the SKY insert with three alanine residues (AAA) or deletion of the insert (ΔSKY) did not substantially alter the fold or thermal stability of the protein. Replacing SKY with a canonical turn (ΔSKYD49G) introduced significant conformational heterogeneity by NMR that was removed upon deletion of a known regulatory region, the FIS1 arm. Expression of AAA fragmented mitochondria into perinuclear clumps associated with increased mitochondrial DRP1 similar to the wild-type protein. In contrast, the expression of ΔSKY variants led to elongated mitochondrial networks and reduced mitochondrial DRP1 by colocalization analysis, although DRP1 coimmunoprecipitates were highly enriched with ΔSKY variants. Co-expression of YFP-TBC1D15 with ΔSKY variants rescued mitochondrial morphology, despite a reduced ability to drive YFP-TBC1D15 into punctate structures that is found upon co-expression with wildtype FIS1 or the AAA variant. In support YFP-TBC1D15 coimmunoprecipitates were poorly enriched with ΔSKY variants. Co-expression of YFP-TBC1D15 also revealed a gain of function phenotype with the AAA variant compared to wildtype. Collectively these results show that FIS1 can be modulated by conserved residues, thus supporting a unifying model whereby FIS1 activity is effectively governed by intramolecular interactions between the regulatory FIS1 arm and an S-X-X insert that is conserved across eukaryotes.

Keywords: Mitochondria; dynamin; fission; mitophagy; nuclear magnetic resonance (NMR); organelle dynamic; peroxisome; protein motif; repeat proteins; tetratricopeptide repeat

DOI: https://doi.org/10.1016/j.jbc.2023.105303

Free Radic Biol Med. 2023 Sep 25. pii: S0891-5849(23)00654-8. [Epub ahead of print]208 771-779

The glyoxylate shunt protein ICL-1 protects from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response.

Guoqiang Wang, Ricardo Laranjeiro, Stephanie LeValley, Jeremy M Van Raamsdonk, Monica Driscoll.

Disrupting mitochondrial superoxide dismutase (SOD) causes neonatal lethality in mice and death of flies within 24 h after eclosion. Deletion of mitochondrial sod genes in C. elegans impairs fertility as well, but surprisingly is not detrimental to survival of progeny generated. The comparison of metabolic pathways among mouse, flies and nematodes reveals that mice and flies lack the glyoxylate shunt, a shortcut that bypasses part of the tricarboxylic acid (TCA) cycle. Here we show that ICL-1, the sole protein that catalyzes the glyoxylate shunt, is critical for protection against embryonic lethality resulting from elevated levels of mitochondrial superoxide. In exploring the mechanism by which ICL-1 protects against ROS-mediated embryonic lethality, we find that ICL-1 is required for the efficient activation of mitochondrial unfolded protein response (UPRmt) and that ATFS-1, a key UPRmt transcription factor and an activator of icl-1 gene expression, is essential to limit embryonic/neonatal lethality in animals lacking mitochondrial SOD. In sum, we identify a biochemical pathway that highlights a molecular strategy for combating toxic mitochondrial superoxide consequences in cells.

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.09.029

Nat Rev Mol Cell Biol. 2023 Oct 02.

Mechanisms and regulation of human mitochondrial transcription.

Benedict G Tan, Claes M Gustafsson, Maria Falkenberg.

The expression of mitochondrial genes is regulated in response to the metabolic needs of different cell types, but the basic mechanisms underlying this process are still poorly understood. In this Review, we describe how different layers of regulation cooperate to fine tune initiation of both mitochondrial DNA (mtDNA) transcription and replication in human cells. We discuss our current understanding of the molecular mechanisms that drive and regulate transcription initiation from mtDNA promoters, and how the packaging of mtDNA into nucleoids can control the number of mtDNA molecules available for both transcription and replication. Indeed, a unique aspect of the mitochondrial transcription machinery is that it is coupled to mtDNA replication, such that mitochondrial RNA polymerase is additionally required for primer synthesis at mtDNA origins of replication. We discuss how the choice between replication-primer formation and genome-length RNA synthesis is controlled at the main origin of replication (OriH) and how the recent discovery of an additional mitochondrial promoter (LSP2) in humans may change this long-standing model.

DOI: https://doi.org/10.1038/s41580-023-00661-4

Cold Spring Harb Perspect Med. 2023 Oct 03. pii: a041199. [Epub ahead of print]

Mitochondrial Targeted Interventions for Aging.

Sophia Z Liu, Ying Ann Chiao, Peter S Rabinovitch, David J Marcinek.

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.

DOI: https://doi.org/10.1101/cshperspect.a041199

Basic Res Cardiol. 2023 Oct 05. 118(1): 42

Mitophagy for cardioprotection.

Allen Sam Titus, Eun-Ah Sung, Daniela Zablocki, Junichi Sadoshima.

Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

Keywords: Alternative mitophagy; Drp1; Mitochondrial quality control; Mitophagy

DOI: https://doi.org/10.1007/s00395-023-01009-x