bims-mitran 2022-02-27 papers

Issue of 2022–02–27
two papers selected by
Andreas Kohler, Stockholm University

Biomedicines. 2022 Feb 18. pii: 490. [Epub ahead of print]10(2):

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics.

Sanjana Saravanan, Caitlin J Lewis, Bhavna Dixit, Matthew S O'Connor, Alexandra Stolzing, Amutha Boominathan.

Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome's transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging.

Keywords: allotopic expression; gene therapy; mitochondria; mitochondrial diseases; mtDNA; mtDNA editing; mtDNA mutations

DOI: https://doi.org/10.3390/biomedicines10020490

Genome Res. 2022 Feb 22.

Low-input RNase footprinting for simultaneous quantification of cytosolic and mitochondrial translation.

Qianru Li, Haiwang Yang, Emily K Stroup, Hongbin Wang, Zhe Ji.

We describe a low-input RNase footprinting approach for the rapid quantification of ribosome-protected fragments with as few as 1000 cultured cells. The assay uses a simplified procedure to selectively capture ribosome footprints based on optimized RNase digestion. It simultaneously maps cytosolic and mitochondrial translation with single-nucleotide resolution. We applied it to reveal selective functions of the elongation factor TUFM in mitochondrial translation, as well as synchronized repression of cytosolic translation after TUFM perturbation. We show the assay is applicable to small amounts of primary tissue samples with low protein synthesis rates, including snap-frozen tissues and immune cells from an individual's blood draw. We showed its feasibility to characterize the personalized immuno-translatome. Our analyses revealed that thousands of genes show lower translation efficiency in monocytes compared with lymphocytes, and identified thousands of translated noncanonical open reading frames (ORFs). Altogether, our RNase footprinting approach opens an avenue to assay transcriptome-wide translation using low-input samples from a wide range of physiological conditions.

DOI: https://doi.org/10.1101/gr.276139.121