SLC-30A9 is required for Zn ²⁺ homeostasis, Zn ²⁺ mobilization, and mitochondrial health

Abstract

The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn²⁺ store, and excessive mitochondrial Zn²⁺ is linked to neurodegeneration. How mitochondria maintain their Zn²⁺ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn²⁺ from mitochondria in both <i>Caenorhabditis elegans</i> and human cells. Loss of <i>slc-30a9</i> leads to elevated Zn²⁺ 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 <i>C. elegans</i>, during which Zn²⁺ exits from mitochondria and acts as an activation signal. In <i>slc-30a9</i>-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an <i>SLC30A9</i> mutation was found.