title: Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress.
abstract: Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.
authors: Department of Pediatrics/Neonatology, University of California San Francisco, San Francisco, California, United States of America.
authors: Kurosh
authors: K
authors: Ameri
authors: Anthony M
authors: AM
authors: Rajah
authors: Vien
authors: V
authors: Nguyen
authors: Timothy A
authors: TA
authors: Sanders
authors: Arman
authors: A
authors: Jahangiri
authors: Michael
authors: M
authors: Delay
authors: Matthew
authors: M
authors: Donne
authors: Hwa J
authors: HJ
authors: Choi
authors: Kathryn V
authors: KV
authors: Tormos
authors: Yerem
authors: Y
authors: Yeghiazarians
authors: Stefanie S
authors: SS
authors: Jeffrey
authors: Paolo F
authors: PF
authors: Rinaudo
authors: David H
authors: DH
authors: Rowitch
authors: Manish
authors: M
authors: Aghi
authors: Emin
authors: E
authors: Maltepe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D013312:Stress, Physiological; D014183:Transplantation, Heterologous; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C405619:HIGD1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
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