AMPK–FOXO–IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations

Author:

Zhang Hu1ORCID,Zhu Yunan1ORCID,Suehiro Yuji2ORCID,Mitani Shohei2ORCID,Xue Ding1ORCID

Affiliation:

1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309

2. Department of Physiology, Tokyo Women’s Medical University, School of Medicine, Tokyo 162-8666, Japan

Abstract

Pathological mutations in human mitochondrial genomes (mtDNA) can cause a series of neurological, behavioral, and developmental defects, but the underlying molecular mechanisms are poorly understood. We show here that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway plays a key role in mediating similar defects caused by different mtDNA mutations in Caenorhabditis elegans , including loss or reduction of osmotic, chemical and olfactory sensing, locomotion, and associative learning and memory, as well as increased embryonic lethality. mtDNA mutations cause reduced ATP (adenosine triphosphate) levels, activation of C. elegans AMPK AAK-2, and nuclear translocation of the FOXO transcription factor DAF-16. Activated DAF-16 up-regulates the expression of inositol triphosphate receptor ITR-1, an endoplasmic reticulum calcium channel, leading to increased basal cytosolic Ca 2+ levels, decreased neuronal responsiveness, compromised synapses, and increased embryonic death. Treatment of mtDNA mutants with vitamin MK-4 restores cellular ATP and cytosolic Ca 2+ levels, improves synaptic development, and suppresses sensory and behavioral defects and embryonic death. Our study provides crucial mechanistic insights into neuronal and developmental defects caused by mtDNA mutations and will improve understanding and treatment of related mitochondrial diseases.

Funder

HHS | NIH | National Institute of General Medical Sciences

March of Dimes Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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