bims-nenemi 2025-08-24 papers

Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.

Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.

Keywords: metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides

DOI: https://doi.org/10.1042/10.1042/BCJ20253237

Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):

High tide or low tide: the transport and metabolism of mitochondrial nucleotides.

Thomas MacVicar.

Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.

Keywords: metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides

DOI: https://doi.org/10.1042/BCJ20253237

Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2402291121

Mitochondrial genome copy number variation across tissues in mice and humans.

Sneha P Rath, Rahul Gupta, Ellen Todres, Hong Wang, Alexis A Jourdain, Kristin G Ardlie, Sarah E Calvo, Vamsi K Mootha.

The mammalian mitochondrial genome (mtDNA) is multicopy and its copy number (mtCN) varies widely across tissues, in development and in disease. Here, we systematically catalog this variation by assaying mtCN in 52 human tissues across 952 donors (10,499 samples from the Genotype-Tissue Expression project) and 20 murine tissues using qPCR, capturing 50- and 200-fold variation, respectively. We also estimate per cell mtCN across 173 human cell lines from the Cancer Cell Line Encyclopedia using whole-genome sequencing data and observe >50-fold variation. We then leverage the vast amount of genomics data available for these repositories to credential our resource and uncover mtDNA-related biology. Using already existing proteomics data, we show that variation in mtCN can be predicted by variation in TFAM, histone, and mitochondrial ribosome protein abundance. We also integrate mtCN estimates with the CRISPR gene dependency measurements to find that cell lines with high mtCN are resistant to loss of GPX4, a glutathione phospholipid hydroperoxidase. Our resource captures variation in mtCN across mammalian tissues and should be broadly useful to the research community.

Keywords: GPX4; TFAM; histone; mitochondrial ribosome; mtDNA

DOI: https://doi.org/10.1073/pnas.2402291121