CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Using a mouse genetic approach, this work demonstrated for the first time that Cisd2 is involved in mammalian life span control. Cisd2 deficiency in mice leads to mitochondrial breakdown and dysfunction; this is accompanied by cell death with autophagic features and these events precede the two earliest manifestations of nerve and muscle degeneration. Together, they lead to a panel of phenotypic features suggestive of premature aging. This work effectively links Cisd2 gene function, mitochondrial integrity and aging in mammals.