Pseudohypoxia-Stabilized HIF2α Transcriptionally Inhibits <i>MNRR1</i>, a Druggable Target in MELAS.

ABSTRACT: The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound

SUBMITTER: Purandare N 

PROVIDER: S-EPMC12293968 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature