bims-mitran 2024-06-16 papers

Issue of 2024–06–16
four papers selected by
Andreas Kohler, Umeå University

Trends Cell Biol. 2024 Jun 08. pii: S0962-8924(24)00097-7. [Epub ahead of print]

Unique architectural features of mammalian mitochondrial protein synthesis.

Oliver Rackham, Martin Saurer, Nenad Ban, Aleksandra Filipovska.

Mitochondria rely on coordinated expression of their own mitochondrial DNA (mtDNA) with that of the nuclear genome for their biogenesis. The bacterial ancestry of mitochondria has given rise to unique and idiosyncratic features of the mtDNA and its expression machinery that can be specific to different organisms. In animals, the mitochondrial protein synthesis machinery has acquired many new components and mechanisms over evolution. These include several new ribosomal proteins, new stop codons and ways to recognise them, and new mechanisms to deliver nascent proteins into the mitochondrial inner membrane. Here we describe the mitochondrial protein synthesis machinery in mammals and its unique mechanisms of action elucidated to date and highlight the technologies poised to reveal the next generation of discoveries in mitochondrial translation.

Keywords: RNA; mitochondria; mitochondrial disease; ribosomes; translation

DOI: https://doi.org/10.1016/j.tcb.2024.05.001

Front Cell Dev Biol. 2024 ;12 1410245

Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.

Álvaro Antolínez-Fernández, Paula Esteban-Ramos, Miguel Ángel Fernández-Moreno, Paula Clemente.

Mitochondria play a central role in cellular metabolism producing the necessary ATP through oxidative phosphorylation. As a remnant of their prokaryotic past, mitochondria contain their own genome, which encodes 13 subunits of the oxidative phosphorylation system, as well as the tRNAs and rRNAs necessary for their translation in the organelle. Mitochondrial protein synthesis depends on the import of a vast array of nuclear-encoded proteins including the mitochondrial ribosome protein components, translation factors, aminoacyl-tRNA synthetases or assembly factors among others. Cryo-EM studies have improved our understanding of the composition of the mitochondrial ribosome and the factors required for mitochondrial protein synthesis and the advances in next-generation sequencing techniques have allowed for the identification of a growing number of genes involved in mitochondrial pathologies with a defective translation. These disorders are often multisystemic, affecting those tissues with a higher energy demand, and often present with neurodegenerative phenotypes. In this article, we review the known proteins required for mitochondrial translation, the disorders that derive from a defective mitochondrial protein synthesis and the animal models that have been established for their study.

Keywords: OxPhos; mitochondria; mitochondrial disorders; mitoribosome; translation

DOI: https://doi.org/10.3389/fcell.2024.1410245

Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.

Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

Keywords: IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA

DOI: https://doi.org/10.1016/j.cell.2024.05.017

J Physiol Biochem. 2024 Jun 12.

Epigenetic reprogramming of mtDNA and its etiology in mitochondrial diseases.

Anil Kumar, Anita Choudhary, Anjana Munshi.

Mitochondrial functionality and its regulation are tightly controlled through a balanced crosstalk between the nuclear and mitochondrial DNA interactions. Epigenetic signatures like methylation, hydroxymethylation and miRNAs have been reported in mitochondria. In addition, epigenetic signatures encoded by nuclear DNA are also imported to mitochondria and regulate the gene expression dynamics of the mitochondrial genome. Alteration in the interplay of these epigenetic modifications results in the pathogenesis of various disorders like neurodegenerative, cardiovascular, metabolic disorders, cancer, aging and senescence. These modifications result in higher ROS production, increased mitochondrial copy number and disruption in the replication process. In addition, various miRNAs are associated with regulating and expressing important mitochondrial gene families like COX, OXPHOS, ND and DNMT. Epigenetic changes are reversible and therefore therapeutic interventions like changing the target modifications can be utilized to repair or prevent mitochondrial insufficiency by reversing the changed gene expression. Identifying these mitochondrial-specific epigenetic signatures has the potential for early diagnosis and treatment responses for many diseases caused by mitochondrial dysfunction. In the present review, different mitoepigenetic modifications have been discussed in association with the development of various diseases by focusing on alteration in gene expression and dysregulation of specific signaling pathways. However, this area is still in its infancy and future research is warranted to draw better conclusions.

Keywords: Epigenetics; Hydroxymethylation; Methylation; miRNAs; mito-miRNAs; mt-DNA

DOI: https://doi.org/10.1007/s13105-024-01032-z