bims-mitpro 2024-02-25 papers

Issue of 2024–02–25
six papers selected by
Andreas Kohler, Umeå University

Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805

Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.

The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.

Keywords: CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein

DOI: https://doi.org/10.1016/j.celrep.2024.113805

Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772

Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.

Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.

The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.

Keywords: CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain

DOI: https://doi.org/10.1016/j.celrep.2024.113772

Rev Neurosci. 2024 Feb 19.

Mitochondria and MICOS - function and modeling.

Haym Benaroya.

An extensive review is presented on mitochondrial structure and function, mitochondrial proteins, the outer and inner membranes, cristae, the role of F1FO-ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS), the sorting and assembly machinery morphology and function, and phospholipids, in particular cardiolipin. Aspects of mitochondrial regulation under physiological and pathological conditions are outlined, in particular the role of dysregulated MICOS protein subunit Mic60 in Parkinson's disease, the relations between mitochondrial quality control and proteins, and mitochondria as signaling organelles. A mathematical modeling approach of cristae and MICOS using mechanical beam theory is introduced and outlined. The proposed modeling is based on the premise that an optimization framework can be used for a better understanding of critical mitochondrial function and also to better map certain experiments and clinical interventions.

Keywords: MICOS; Mic60; cristae; metabolism; mitochondria; physiology

DOI: https://doi.org/10.1515/revneuro-2024-0004

Cell Death Differ. 2024 Feb 23.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

DOI: https://doi.org/10.1038/s41418-024-01260-2

Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874

MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.

Kostas Tokatlidis.

Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.

DOI: https://doi.org/10.1016/j.celrep.2024.113874

Redox Biol. 2024 Feb 13. pii: S2213-2317(24)00063-6. [Epub ahead of print]71 103087

METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.

Hao Li, Kailun Yu, Huilong Hu, Xiandan Zhang, Siyu Zeng, Jiawen Li, Xiaoning Dong, Xusheng Deng, Jianhui Zhang, Yongyou Zhang.

Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role of mitochondria in ferroptosis regulation, the underlying mechanisms remain elusive. This study reveals that the mitochondrial protein METTL17 governs mitochondrial function in colorectal cancer (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes that METTL17 expression positively correlates with ferroptosis resistance in cancer cells and is up-regulated in CRC. Depletion of METTL17 sensitizes CRC cells to ferroptosis, impairs cell proliferation, migration, invasion, xenograft tumor growth, and AOM/DSS-induced CRC tumorigenesis. Furthermore, suppression of METTL17 disrupts mitochondrial function, energy metabolism, and enhances intracellular and mitochondrial lipid peroxidation and ROS levels during ferroptotic stress. Mechanistically, METTL17 inhibition significantly reduces mitochondrial RNA methylation, including m4C, m5C, m3C, m7G, and m6A, leading to impaired translation of mitochondrial protein-coding genes. Additionally, the interacting proteins associated with METTL17 are essential for mitochondrial gene expression, and their knockdown sensitizes CRC cells to ferroptosis and inhibits cell proliferation. Notably, combined targeting of METTL17 and ferroptosis in a therapeutic approach effectively suppresses CRC xenograft growth in vivo. This study uncovers the METTL17-mediated defense mechanism for cell survival and ferroptosis in mitochondria, highlighting METTL17 as a potential therapeutic target for CRC.

Keywords: Colorectal cancer (CRC); Ferroptosis; METTL17; Mitochondrial RNA methylation

DOI: https://doi.org/10.1016/j.redox.2024.103087