Open AccessInositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling
Author(s) -
Latika Nagpal,
Michael D. Kornberg,
Solomon H. Snyder
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2121946119
Subject(s) - mitophagy , inositol , mitochondrion , pink1 , microbiology and biotechnology , pyrophosphate , neuroprotection , mitochondrial fission , kinase , biology , biochemistry , enzyme , chemistry , receptor , neuroscience , autophagy , apoptosis
Significance Inositol pyrophosphates are versatile messenger molecules containing the energetic pyrophosphate bond. One of the principal enzymes generating the inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate) is inositol hexakisphosphate kinase 2 (IP6K2). Previous work has shown that IP6K2 is neuroprotective and maintains mitochondrial respiration. We now report that loss of IP6K2 leads to increased mitochondrial fission and mitophagy. Regulation of mitochondrial dynamics by IP6K2 depends on the protein PINK1 and, interestingly, is independent of IP6K2 enzymatic activity. These findings provide mechanistic insight into the regulation of mitochondrial function by IP6K2, which has implications for neuroprotection and mitochondrial physiology more generally.