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

Proc Natl Acad Sci U S A. 2021 Aug 31;118(35):e2023909118. doi: 10.1073/pnas.2023909118.

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.

Keywords: Birk–Landau–Perez cerebrorenal syndrome; SLC-30A9; Zn2+ transporters; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / physiology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / pharmacology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / pharmacology*
  • Dendrites / metabolism
  • Female
  • Gene Knockout Techniques
  • HeLa Cells
  • Homeostasis
  • Humans
  • Male
  • Membrane Potential, Mitochondrial
  • Mitochondria / metabolism*
  • Mutation
  • Spermatozoa / physiology
  • Transcription Factors / genetics
  • Transcription Factors / pharmacology*
  • Zinc / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Cation Transport Proteins
  • Cell Cycle Proteins
  • SLC30A9 protein, human
  • Transcription Factors
  • Zinc