Werner, E., Gokhale, A., Ackert, M., Xu, C., Wen, Z., Roberts, A.M., Roberts, B.R., Vrailas-Mortimer, A., Crocker, A., Faundez, V. (2022). The mitochondrial RNA granule modulates manganese-dependent cell toxicity.  Mol. Biol. Cell 33(12): ar108.

FBrf0254547

Research paper

Prolonged manganese exposure causes manganism, a neurodegenerative movement disorder. The identity of adaptive and nonadaptive cellular processes targeted by manganese remains mostly unexplored. Here we study mechanisms engaged by manganese in genetic cellular models known to increase susceptibility to manganese exposure, the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson's gene PARK2. We found that SLC30A10 and PARK2 mutations as well as manganese exposure compromised the mitochondrial RNA granule composition and function, resulting in disruption of mitochondrial transcript processing. These RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, cells that survived a cytotoxic manganese challenge had impaired RNA granule function, thus suggesting that this granule phenotype was adaptive. CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 or DHX30, as well as pharmacological inhibition of mitochondrial transcription-translation, were protective rather than deleterious for survival of cells acutely exposed to manganese. Similarly, adult Drosophila mutants with defects in the mitochondrial RNA granule component scully were safeguarded from manganese-induced mortality. We conclude that impairment of the mitochondrial RNA granule function is a protective mechanism for acute manganese toxicity.

PMC9635304 (PMC) (EuropePMC)