Complex I and II are required for normal mitochondrial Ca²⁺ homeostasis

Cytosolic calcium (_cCa²⁺) entry into mitochondria is facilitated by the mitochondrial membrane potential (ΔΨm), an electrochemical gradient generated by the electron transport chain (ETC). Is has been assumed that as long as mutations that affect the ETC do not affect the ΔΨm, the mitochondrial Ca²⁺ (_mCa²⁺) homeostasis remains normal. We show that knockdown of NDUFAF3 and SDHB reduce ETC activity altering _mCa²⁺ efflux and influx rates while ΔΨm remains intact. Shifting the equilibrium toward lower [Ca²⁺]_m accumulation renders cells resistant to death. Our findings reveal an unexpected relationship between complex I and II with the _mCa²⁺ homeostasis independent of ΔΨm.