Hexokinase activity is required for recruitment of parkin to depolarized mitochondria
Open accessAbstract
Autosomal recessive parkinsonism genes contribute to maintenance of mitochondrial function. Two of these, PINK1 and parkin, act in a pathway promoting autophagic removal of depolarized mitochondria. Although recruitment of parkin to mitochondria is PINK1-dependent, additional components necessary for signaling are unclear. We performed a screen for endogenous modifiers of parkin recruitment to depolarized mitochondria and identified hexokinase 2 (HK2) as a novel modifier of depolarization-induced parkin recruitment. Hexose kinase activity was required for parkin relocalization, suggesting the effects are shared among hexokinases including the brain-expressed hexokinase 1 (HK1). Knockdown of both HK1 and HK2 led to a stronger block in parkin relocalization than either isoform alone, and expression of HK2 in primary neurons promoted YFP-parkin recruitment to depolarized mitochondria. Mitochondrial parkin recruitment was attenuated with AKT inhibition, which is known to modulate HK2 activity and mitochondrial localization. We, therefore, propose that Akt-dependent recruitment of hexokinases is a required step in the recruitment of parkin prior to mitophagy.
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Multiple genome-wide siRNA/CRISPR-Cas9 screens have identified mitophagy genes with little overlap between studies.
“Multiple genome-wide siRNA/CRISPR-Cas9 screens have already identified mitophagy genes although with little overlap between studies [15–18].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [17]
The high-content screen section describes a genome-wide shRNA screen that identified HK2 as a modifier of parkin recruitment before mitophagy, so this paper supports the cited group of studies as an example of a gene-finding screen. It used shRNA rather than siRNA or CRISPR-Cas9, and our copy does not establish that the genes identified by different screens had little overlap. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAkt-mediated activation of HK2 is required for its translocation to damaged mitochondria and subsequent recruitment of Parkin to initiate mitophagy.
“Furthermore, it was recently suggested that ROCK inhibits Parkin-mediated mitophagy via PTEN antagonization of the PI3K/Akt pathway [139] as Akt-mediated activation of hexokinase 2 (HK2) is required for its translocation to damaged mitochondria and subsequent recruitment of Parkin to initiate mitophagy [139,140] (Figure 3).”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [140]
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Cites
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
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Self-citationPINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
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“Parkin has been shown to be recruited to the OMM in many studies (3,8,12,17,18,20,29,30,42,43).”
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Cited by
Sorted by citations
The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
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miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00029-w
- Authors
- McCoy, M. K., Kaganovich, A., Rudenko, I. N., Ding, J., & Cookson, M. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cookson, Mark R.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-08-19
- Volume
- 23
- Issue
- 1
- Pages
- 145-156
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3857951
- OpenAlex
- W2144314949
- Cited by
- 97
- References
- 7
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 12
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Human Molecular Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Parkin, hexokinase 2, hexokinase 1, PINK1, mitochondrial depolarization, mitophagy, Akt signaling, autosomal recessive parkinsonism, primary neurons
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Cells, Cultured, HeLa Cells, Hexokinase, Humans, Mice, Inbred C57BL, Mitochondria, Neurons, Phosphorylation, Protein Kinases, Signal Transduction, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-akt, Mice, Gene Knockdown Techniques, Mitophagy
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