Hexokinase activity is required for recruitment of parkin to depolarized mitochondria

• Published in: Human molecular genetics 2014-01, Vol.23 (1), p.145-156
• Main Authors: McCoy, Melissa K, Kaganovich, Alice, Rudenko, Iakov N, Ding, Jinhui, Cookson, Mark R
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Cells, Cultured; Gene Knockdown Techniques; HeLa Cells; Hexokinase - genetics; Hexokinase - metabolism; Humans; Mice; Mice, Inbred C57BL; Mitochondria - physiology; Mitochondrial Degradation; Neurons - metabolism; Phosphorylation; Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt407

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.