Heat-induced calcium leakage causes mitochondrial damage in caenorhabditis elegans body-wall muscles

Kenta Momma, Takashi Homma, Ruri Isaka, Surabhi Sudevan, Atsushi Higashitani

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. Here, we showed that elevated temperature increases free cytosolic Ca2+ [Ca2+ ]f from RYR (ryanodine receptor)/UNC-68 in vivo in the muscles of an experimental model animal, the nematode Caenorhabditis elegans. This subsequently leads to mitochondrial fragmentation and dysfunction, and breakdown of myofilaments similar to rhabdomyolysis. In addition, treatment with an inhibitor of RYR (dantrolene) or activation of FoxO (Forkhead box O)/DAF-16 is effective against heat-induced muscle damage. Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. To gain insight into heat-induced muscle breakdown, we investigated alterations of Ca2+ homeostasis and mitochondrial morphology in vivo in body-wall muscles of C. elegans exposed to elevated temperature. Heat stress for 3 hr at 35° increased the concentration of [Ca2+ ]f, and led to mitochondrial fragmentation and subsequent dysfunction in the muscle cells. A similar mitochondrial fragmentation phenotype is induced in the absence of heat stress by treatment with a calcium ionophore, ionomycin. Mutation of the unc-68 gene, which encodes the ryanodine receptor that is linked to Ca2+ release from the sarcoplasmic reticulum, could suppress the mitochondrial dysfunction, muscle degeneration, and reduced mobility and life span induced by heat stress. In addition, in a daf-2 mutant, in which the DAF-16/FoxO transcription factor is activated, resistance to calcium overload, mitochondrial fragmentation, and dysfunction was observed. These findings reveal that heat-induced Ca2+ accumulation causes mitochondrial damage and consequently induces muscle breakdown.

    Original languageEnglish
    Pages (from-to)1985-1994
    Number of pages10
    JournalGenetics
    Volume206
    Issue number4
    DOIs
    Publication statusPublished - 2017 Jan 1

    Keywords

    • Calcium
    • DAF-16
    • Heat stress
    • Mitochondrial fragmentation
    • Ryanodine receptor

    ASJC Scopus subject areas

    • Genetics

    Fingerprint Dive into the research topics of 'Heat-induced calcium leakage causes mitochondrial damage in caenorhabditis elegans body-wall muscles'. Together they form a unique fingerprint.

  • Cite this