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Abstract
Zn2+ is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn2+ level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn2+. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn2+ exporter. Loss of SLC-30A9 leads to mitochondrial Zn2+ accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn2+ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn2+ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn2+ pool from which mitochondrial Zn2+ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn2+ levels for normal mitochondrial structure and functions.
Highlights
IntroductionZn2+ plays important roles in a wide range of physiological and cellular processes such as development, metabolism, DNA synthesis, and transcription (Colvin et al, 2010; Kambe et al, 2015)
Zinc, in the ion form (Zn2+), is an essential trace element for organisms
To identify regulators that are important for mitochondrial homeostasis, we performed genetic screens to search for mutants that display abnormal mitochondrial morphology, using C. elegans adult animals carrying an integrated array that expresses mitochondrion-targeted GFP (MitoGFP) in hypodermal cells (Zhou et al, 2019; Tang et al, 2020)
Summary
Zn2+ plays important roles in a wide range of physiological and cellular processes such as development, metabolism, DNA synthesis, and transcription (Colvin et al, 2010; Kambe et al, 2015). Zn2+ functions as an important signaling ion (Frederickson et al, 2005; Yamasaki et al, 2007; Fukada et al, 2011). Intracellular Zn2+ promotes the expression and secretion of nerve growth factor (NGF) and early growth response factor 1 (EGR1), and promotes the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) (Park and Koh, 1999). Zn2+ deficiency has been found to associate with poor growth and development, congenital neurological and immune disorders, defective wound healing, chronic inflammation, alopecia, persistent diarrhea, and bleeding (Kambe et al, 2015; Mammadova-Bach and Braun, 2019), to name a few. Zn2+ accumulation is known to potently induce neuronal cell death in ischemia and blunt head trauma, and is associated with Alzheimer’s disease (AD) (Sensi et al, 2009)
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