HIGD1A

HIGD1A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LOM
Identifiers
Aliases	HIGD1A , HIG1, RCF1a, HIG1 hypoxia inducible domain family member 1A
External IDs	MGI: 1930666 HomoloGene: 121937 GeneCards: HIGD1A
Gene location (Human) Chr. Chromosome 3 (human) [1] Band 3p22.1 Start 42,782,908 bp [1] End 42,804,490 bp [1]
Gene location (Mouse) Chr. Chromosome 9 (mouse) [2] Band 9|9 F4 Start 121,848,563 bp [2] End 121,858,362 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in rectum gastric mucosa Brodmann area 9 cingulate gyrus smooth muscle tissue prefrontal cortex right lobe of liver islet of Langerhans right coronary artery anterior pituitary Top expressed in facial motor nucleus Region I of hippocampus proper medial vestibular nucleus ventral tegmental area habenula dorsal tegmental nucleus mammillary body interventricular septum endocardial cushion atrioventricular valve More reference expression data BioGPS More reference expression data
Orthologs Species Human Mouse 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 NP_062788 NP_001344766 NP_001344767 NP_001344768 NP_001344769 NP_001344770 Location (UCSC) Chr 3: 42.78 – 42.8 Mb Chr 9: 121.85 – 121.86 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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:

• AIF, ^[10]
• γ-secretase ^[11] and
• OPA1. ^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000181061 - Ensembl, May 2017
2. 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. 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. 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. 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. 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

• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi: 10.1101/gr.6.9.791 . PMID   8889548.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Denko N, Schindler C, Koong A, Laderoute K, Green C, Giaccia A (Feb 2000). "Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment". Clinical Cancer Research. 6 (2): 480–7. PMID   10690527.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC   310948 . PMID   11076863.
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC   1083732 . PMID   11256614.
• Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S (Sep 2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC   515316 . PMID   15342556.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC   528930 . PMID   15489336.
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. doi:10.1093/nar/gkj139. PMC   1347501 . PMID   16381901.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.