SLC-30A9 is required for Zn homeostasis, Zn mobilization, and mitochondrial health.

The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn store, and excessive mitochondrial Zn is linked to neurodegeneration. How mitochondria maintain their Zn homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn from mitochondria in both and human cells. Loss of leads to elevated Zn levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in , during which Zn exits from mitochondria and acts as an activation signal. In -deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an mutation was found.