Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease

Abstract

A subset of mitochondrial tRNAs (mt-tRNAs) contains taurine-derived modifications at 34U of the anticodon. Loss of taurine modification has been linked to the development of mitochondrial diseases, but the molecular mechanism is still unclear. Here, we showed that taurine modification is catalyzed by mitochondrial optimization 1 (Mto1) in mammals. Mto1 deficiency severely impaired mitochondrial translation and respiratory activity. Moreover, Mto1-deficient cells exhibited abnormal mitochondrial morphology owing to aberrant trafficking of nuclear DNA-encoded mitochondrial proteins, including Opa1. The mistargeted proteins were aggregated and misfolded in the cytoplasm, which induced cytotoxic unfolded protein response. Importantly, application of chemical chaperones successfully suppressed cytotoxicity by reducing protein misfolding and increasing functional mitochondrial proteins in Mto1-deficient cells and mice. Thus, our results demonstrate the essential role of taurine modification in mitochondrial translation and reveal an intrinsic protein homeostasis network between the mitochondria and cytosol, which has therapeutic potential for mitochondrial diseases.

Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency

“…Furthermore, MMA cells display decreased mitochondrial membrane potential and reduced mitochondrial bioenergetics. These dysfunctions result in the generation of a large amount of oxygen radicals and cellular stress, which are observed in other mitochondrial diseases 51 . A similar accumulation of morphologically aberrant and dysfunctional mitochondria is observed in the kidney tubule cells of Mmut KO/KI mice, demonstrating the key role of MMUT function for the mitochondrial network homeostasis and function.…”

Noninvasive diagnosis of TRIT1‐related mitochondrial disorder by measuring i6A37 and ms2i6A37 modifications in tRNAs from blood and urine samples

“…From a therapeutic standpoint, tauroursodeoxycholic acid (TUDCA), an FDA‐approved agent for the treatment of cholestatic liver diseases, has been shown to suppress cytotoxicity in cells with hypomodified mt‐tRNA (Fakruddin et al, ). The further accumulation of clinical evidence is awaited to determine whether such drugs might benefit patients with TRIT1 ‐related disorders.…”

Impaired bile acid metabolism with defectives of mitochondrial-tRNA taurine modification and bile acid taurine conjugation in the taurine depleted cats

“…Taurine-modified mt-tRNA analysis. Taurine modification of mt-tRNA was examined by using mass spectrometry, as previously described 34 . In brief, total RNA was isolated from cat liver tissues by using TRIzol reagent, based on the manufacturer's instruction.…”

“…Impaired taurine modification with mt-tRNAs causes certain inherited mitochondrial diseases; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and myoclonus epilepsy with ragged red fibers (MERRF) 33 . Mitochondrial diseases occur because of specific point mutations in the region of mitochondrial deoxyribonucleic acid (mt-DNA) that codes for tRNAs, although impaired taurine modification with mt-tRNAs may also be caused by taurine depletion 33,34 . Therefore, taurine depletion may impact BA conjugation, as well as BA synthesis, because mitochondrial metabolism is involved in BA synthesis.…”