The Mitochondrial RNA Granule Modulates Manganese-Dependent Cell Toxicity

Abstract

Manganese exposure causes a parkinsonian disorder, manganism, which is viewed as a neurodegenerative disorder minimally related to Parkinson s disease. We tested this hypothesis asking if there is phenotypic and mechanistic overlap between two genetic models of these diseases. We targeted for study the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson gene PARK2. We performed comparative molecular systems studies and found that SLC30A10 and PARK2 mutations compromised the mitochondrial RNA granule as well as mitochondrial transcript processing. These shared RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 and DHX30, or 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 the downregulation of the mitochondrial RNA granule function is a protective mechanism for acute metal toxicity. We propose that initially adaptive mitochondrial dysfunction caused by manganese exposure, when protracted, causes neurodegeneration