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HUMMR, a hypoxia- and HIF-1–inducible protein, alters mitochondrial distribution and transport

¹ Department of Neurology, Center for Neural Development and Disease, ² Interdepartmental Graduate Program in Neuroscience, ³ Interdepartmental Graduate Program in Biomedical Genetics, and ⁴ Department of Anesthesiology, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642
⁵ Georgetown University Medical Center, Washington, DC 20057
⁶ Department of Microbiology, Tumour and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden

Correspondence to David A. Rempe: david_rempe{at}urmc.rochester.edu

Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 (HIF-1). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states.

Abbreviations used in this paper: DIV, day in vitro; GRIF-1, GABA_A receptor-interacting factor 1; HIF-1, hypoxia-inducible factor 1 ; HUMMR, hypoxia up-regulated mitochondrial movement regulator; ICC, immunocytochemistry; IMM, inner mitochondrial membrane; IMS, intermembrane space; IP, immunoprecipitation; MLS, mitochondrial localization signal; OMM, outer mitochondrial membrane; scrRNA, scrambled RNA; shRNA, small hairpin RNA; TMD, transmembrane domain.

© 2009 Li et al.
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