Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling
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Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in various cellular functions including neuroprotection. Absence of IP6K2 causes impairment of oxidative phosphorylation regulated by creatine kinase-B. In the present study, we show that IP6K2 is involved in attenuation of PINK1-mediated mitochondrial autophagy (mitophagy) in the brain. Up-regulation of dynamin-related protein (Drp-1), as well as increased expression of mitochondrial biogenesis markers (PGC1-α and NRF-1) in the cerebella of IP6K2-deleted mice (IP6K2-knockout), point to the involvement of IP6K2 in the regulation of mitochondrial fission. Knockdown of IP6K2 also leads to augmented glycolysis, potentially as a compensatory mechanism for decreased mitochondrial respiration. Overexpressing IP6K2 as well as IP6K2-kinase dead mutant in IP6K2-knockdown N2A cells reverses the expression of mitophagy markers, demonstrating that IP6K2-induced mitoprotection is catalytically/kinase independent. IP6K2 supplementation in K2-PINK1 double-knockdown N2A cells fails to reverse the expression of the mitophagic marker, LC3-II, indicating that the mitoprotective effect of IP6K2 is dependent on PINK1. Overall, our study reveals a key neuroprotective role of IP6K2 in the prevention of PINK1-mediated mitophagy in the brain.
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PD-related genes, like Ip6k2, were not concentrated within a cluster of regions but rather distributed across the choroid plexus, cerebellum, SVZ, and visual cortex with limited overlap.
“In contrast, PD-related genes, like the neuroprotective gene Ip6k2 (Nagpal et al., 2022) (Figure 6I), were not concentrated within a cluster of regions but rather distributed across the choroid plexus, cerebellum, SVZ, and visual cortex with limited overlap (Figure 6C).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Nagpal et al., 2022
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Atlas of the aging mouse brain reveals white matter as vulnerable foci
Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.027 · Cited by 213 · see citing works
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- Authors
- Nagpal, L., Kornberg, M. D., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Nagpal, Latika
- Snyder, Solomon H.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2022-03-30
- Volume
- 119
- Issue
- 14
- Pages
- e2121946119-e2121946119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9169102
- OpenAlex
- W4220847815
- Cited by
- 22
- References
- 37
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 8
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | U.S. Public Health Service (MH018501)
- HHS | NIH | National Institute on Drug Abuse (DA044123)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- inositol pyrophosphates, PINK1, mitophagy, mitochondrial fission, Drp1, mitochondrial biogenesis, PGC-1α, NRF1, glycolysis, mitochondrial respiration, neuroprotection, kinase-independent regulation, cerebellum
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Protein Kinases, Signal Transduction, Phosphotransferases (Phosphate Group Acceptor), Mice, Knockout, Mice, Mitophagy
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