Wolfram syndrome is a childhood onset rare genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy unavoidably progressing towards legal blindness before the age of 20. Here we show that WFS1 forms a complex with Neuronal Calcium Sensor 1 (NCS1) and IP3R to promote ER-mitochondrial Ca2+ transfer. In addition, we report that NCS1 localizes to mitochondria-associated membranes and regulates mitochondrial respiratory chain. Importantly, NCS1 overexpression not only restore ER-mitochondria interaction and Ca2+ transfer, but also induces a significant rescue of the dysfunctional mitochondrial phenotype observed in WFS1 deficient cells. Since NCS1 may be targeted by pharmacological molecules, it may be a useful target to treat Wolfram syndrome pharmacologically.