bims-mitpro 2023-12-24 papers

Issue of 2023–12–24
five papers selected by
Andreas Kohler, Umeå University

Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]

Mitochondrial quality control pathways sense mitochondrial protein import.

Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.

Keywords: mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy

DOI: https://doi.org/10.1016/j.tem.2023.11.004

J Biochem. 2023 Dec 15. pii: mvad106. [Epub ahead of print]

Mitochondrial quality control via organelle and protein degradation.

Koji Yamano, Hiroki Kinefuchi, Waka Kojima.

Mitochondria are essential eukaryotic organelles that produce ATP as well as synthesize various macromolecules. They also participate in signaling pathways such as the innate immune response and apoptosis. These diverse functions are performed by >1000 different mitochondrial proteins. Although mitochondria are continuously exposed to potentially damaging conditions such as reactive oxygen species, proteases/peptidases localized in different mitochondrial sub-compartments, termed mitoproteases, maintain mitochondrial quality and integrity. In addition to processing incoming precursors and degrading damaged proteins, mitoproteases also regulate metabolic reactions, mitochondrial protein half-lives, and gene transcription. Impaired mitoprotease function is associated with various pathologies. In this review, we highlight recent advances in our understanding of mitochondrial quality control regulated by autophagy, ubiquitin-proteasomes, and mitoproteases.

Keywords: autophagy; mitophagy; peptidase; protease; ubiquitin

DOI: https://doi.org/10.1093/jb/mvad106

Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]

FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.

Kun Gao, Xiayun Xu, Chenji Wang.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.

Keywords: BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination

DOI: https://doi.org/10.1016/j.molmed.2023.11.017

Int J Mol Sci. 2023 Dec 07. pii: 17209. [Epub ahead of print]24(24):

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.

Eirini Taouktsi, Eleni Kyriakou, Evangelia Voulgaraki, Dimitris Verganelakis, Stefania Krokou, Stamatis Rigas, Gerassimos E Voutsinas, Popi Syntichaki.

p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPKmt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPKmt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPKmt and mitochondrial Unfolded Protein Response (UPRmt) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation.

Keywords: C. elegans; LONP-1; PMK-3; ZIP-2; ageing; heat stress response; mitochondria

DOI: https://doi.org/10.3390/ijms242417209

Biochemistry (Mosc). 2023 Nov;88(11): 1832-1843

Diversity and Evolution of Mitochondrial Translation Apparatus.

Mariya V Baleva, Ulyana E Piunova, Ivan V Chicherin, Sergey A Levitskii, Piotr A Kamenski.

The evolution of mitochondria has proceeded independently in different eukaryotic lines, which is reflected in the diversity of mitochondrial genomes and mechanisms of their expression in eukaryotic species. Mitochondria have lost most of bacterial ancestor genes by transferring them to the nucleus or eliminating them. However, mitochondria of almost all eukaryotic cells still retain relatively small genomes, as well as their replication, transcription, and translation apparatuses. The dependence on the nuclear genome, specific features of mitochondrial transcripts, and synthesis of highly hydrophobic membrane proteins in the mitochondria have led to significant changes in the translation apparatus inherited from the bacterial ancestor, which retained the basic structure necessary for protein synthesis but became more specialized and labile. In this review, we discuss specific properties of translation initiation in the mitochondria and how the evolution of mitochondria affected the functions of main factors initiating protein biosynthesis in these organelles.

Keywords: mitochondria; regulation of translation; translation; translation initiation factors

DOI: https://doi.org/10.1134/S0006297923110135