SLC-30A9 is required for Zn2+ homeostasis, Zn2+ 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 Caenorhabditis elegans and human cells. Loss of slc-30a9 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 C. elegans, during which Zn2+exits from mitochondria and acts as an activation signal. In slc-30a9-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an SLC30A9 mutation was found.