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Abstract
Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).
Highlights
Mitochondria are multi-functional organelles involved in oxidative metabolism, cellular homeostasis, and signal transduction [1,2,3]
In contrast to the increased flow through the citrate cycle (TCA) and ETC, we find significant depletion of genes involved in mitochondrial transport and beta-oxidation of fatty acids, i.e., cytosolic carnitine palmitoyltranferase (Cpt1a), mitochondrial acyl-synthetases (Acsf2, Accs1, Acss3), and 2,4 dienoyl-CoA reductase (Decr1), the latter participating in the beta-oxidation of unsaturated FAs
We have previously shown that brain mitochondria of mice carrying the homozygous knock-in mutation MRPS5 V338Y show impaired mitochondrial function with decreased oxygen consumption, reduced ATP content, and increased levels of reactive oxygen species [11]
Summary
Mitochondria are multi-functional organelles involved in oxidative metabolism, cellular homeostasis, and signal transduction [1,2,3]. As the site of oxidative phosphorylation, mitochondria convert the energy from nutrients into ATP. To perform their key role in cellular energy production, mitochondria use intricate systems that encompass the breakdown of glucose and fatty acids, coupled to oxidative phosphorylation via the citrate cycle (TCA) [4,5]. Mitochondrial diseases are clinically diverse and may manifest in a tissue-specific or multisystemic manner. Most often they affect postmitotic tissues with high energy demands such as brain, skeletal muscle, heart, or cochlea [6,7,8]. The vast majority of proteins essential for mitochondrial function are nuclear encoded; only 13 of the more than 100 different proteins that make up the mitochondrial oxidative system are encoded by mitochondrial DNA and translated by the mitoribosome [9,10]
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