HIGD1A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHIGD1A, HIG1, RCF1a, HIG1 hypoxia inducible domain family member 1A
External IDsMGI: 1930666 HomoloGene: 121937 GeneCards: HIGD1A
Orthologs
SpeciesHumanMouse
Entrez

25994

56295

Ensembl

ENSG00000181061

ENSMUSG00000038412

UniProt

Q9Y241

Q9JLR9

RefSeq (mRNA)

NM_014056
NM_001099668
NM_001099669

NM_019814

RefSeq (protein)

NP_001093138
NP_001093139
NP_054775

Location (UCSC)Chr 3: 42.78 – 42.8 MbChr 9: 121.85 – 121.86 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

HIG1 domain family member 1A (HIGD1A), also known as hypoglycemia/hypoxia inducible mitochondrial protein1-a (HIMP1-a) and hypoxia induced gene 1 (HIG1), is a protein that in humans is encoded by the HIGD1A gene on chromosome 3.[5][6][7][8] This protein promotes mitochondrial homeostasis and survival of cells under stress and is involved in inflammatory and hypoxia-related diseases, including atherosclerosis, ischemic heart disease, and Alzheimer’s disease, as well as cancer.[8][9][10][11]

Structure

The protein encoded by this gene is 10.4 kDa mitochondrial inner membrane protein with two transmembrane domains at the N- and C-terminals.[9][10] These two domains are arranged such that the N- and C-terminals face outward into the intermembrane space while the rest of the protein loops inside the matrix. Though the N-terminal domain is not necessary to direct the localization of HIGD1A, it is required for the survival of the protein.

The gene HIGD1A is an isoform of HIMP1-b via alternative splicing.[9]

Function

HIGD1A primarily functions in mitochondrial homeostasis and, thus, cell survival when under conditions of stress, such as hypoxia and glucose deprivation. For instance, HIGD1A promotes survival of pancreatic α and β cells under stress.[8][9] HIGD1A has also been found in other parts of the brain, heart, liver, and kidney, where it enhances the survival of these organs.[8][11] In macrophages, HIGD1A prevents apoptosis by inhibiting cytochrome C release and caspase activity.[9][10]

HIGD1A is also involved in mitochondrial fusion by regulating OPA1 activity. Its inhibition of the cleavage of OPA1 preserves mitochondrial membrane potential, protects against apoptosis, and maintains ATP levels. Its role in mitochondrial fusion also influences downstream processes such as mtDNA synthesis, cell growth, and cristae organization.[8]

In addition, HIGD1A helps preserve mitochondrial function by regulating mitochondrial γ-secretase activity under hypoxic conditions.[8][11] In the absence of HIGD1A, γ-secretase contributes to the accumulation of amyloid beta in the mitochondria, leading to increased ROS production, mitochondrial dysfunction, and eventually, cell death.[11]

While HIGD1A predominantly contributes to cell survival, it can also promote apoptosis in neurons during the early developmental stages of the central nervous system.[10]

Clinical significance

Since HIGD1A promotes cell survival under hypoxia, the protein protects organs like the heart and brain from hypoxia-related diseases.[9] In particular, HIGD1A localization to the nucleus correlates with the severity of stress in ischemic heart disease, hypoxic-ischemic encephalopathy, and cancer, and thus may serve as a biomarker for these diseases.[10] Moreover, HIGD1A is involved in inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, through its role in macrophage survival.[9] Similarly, HIGD1A could become a key target for treating Alzheimer’s disease by inhibiting γ-secretase, and by extension, amyloid beta production. Notably, HIGD1A inhibits γ-secretase without interfering with Notch cleavage, thus minimizing detrimental side effects from targeting this protein.[11]

Interactions

HIGD1A is known to interact with:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000181061 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038412 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z (Oct 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
  6. ↑ Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
  7. ↑ "Entrez Gene: HIGD1A HIG1 domain family, member 1A".
  8. 1 2 3 4 5 6 7 An HJ, Cho G, Lee JO, Paik SG, Kim YS, Lee H (Aug 2013). "Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria". Proceedings of the National Academy of Sciences of the United States of America. 110 (32): 13014–9. Bibcode:2013PNAS..11013014A. doi:10.1073/pnas.1307170110. PMC 3740888. PMID 23878241.
  9. 1 2 3 4 5 6 7 An HJ, Shin H, Jo SG, Kim YJ, Lee JO, Paik SG, Lee H (Dec 2011). "The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1813 (12): 2088–98. doi:10.1016/j.bbamcr.2011.07.017. PMID 21856340.
  10. 1 2 3 4 5 6 Ameri K, Rajah AM, Nguyen V, Sanders TA, Jahangiri A, Delay M, Donne M, Choi HJ, Tormos KV, Yeghiazarians Y, Jeffrey SS, Rinaudo PF, Rowitch DH, Aghi M, Maltepe E (2013). "Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress". PLOS ONE. 8 (4): e62758. Bibcode:2013PLoSO...862758A. doi:10.1371/journal.pone.0062758. PMC 3639984. PMID 23646141.
  11. 1 2 3 4 5 6 Hayashi H, Nakagami H, Takeichi M, Shimamura M, Koibuchi N, Oiki E, Sato N, Koriyama H, Mori M, Gerardo Araujo R, Maeda A, Morishita R, Tamai K, Kaneda Y (Jun 2012). "HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function". FASEB Journal. 26 (6): 2306–17. doi:10.1096/fj.11-196063. PMID 22355194. S2CID 40000073.

Further reading

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