The Wolfram-like variant WFS1^E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.

ABSTRACT: Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca²⁺) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1^E864K leads to decreases in mitochondria bioenergetics and Ca²⁺ uptake, deregulation of the mitochondrial quality system mechanisms, a

SUBMITTER: Patergnani S 

PROVIDER: S-EPMC11346566 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature