HIGD1A

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 is_associated_with::protein that in humans is encoded by the HIGD1A is_associated_with::gene on chromosome 3. This protein promotes is_associated_with::mitochondrial is_associated_with::homeostasis and survival of cells under stress and is involved in inflammatory and hypoxia-related is_associated_with::diseases, including is_associated_with::atherosclerosis, ischemic is_associated_with::heart disease, and is_associated_with::Alzheimer’s disease, as well as is_associated_with::cancer.

Structure
The protein encoded by this gene is 10.4 kDa mitochondrial inner membrane protein with two is_associated_with::transmembrane domains at the N- and C-terminals. These two domains are arranged such that the N- and C-terminals face outward into the is_associated_with::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 is_associated_with::isoform of HIMP1-b via is_associated_with::alternative splicing.

Function
HIGD1A primarily functions in mitochondrial is_associated_with::homeostasis and, thus, cell survival when under conditions of stress, such as hypoxia and is_associated_with::glucose deprivation. For instance, HIGD1A promotes survival of pancreatic α and β cells under stress. HIGD1A has also been found in other parts of the is_associated_with::brain, is_associated_with::heart, is_associated_with::liver, and is_associated_with::kidney, where it enhances the survival of these organs. In macrophages, HIGD1A prevents apoptosis by inhibiting is_associated_with::cytochrome C release and is_associated_with::caspase activity. HIGD1A is also involved in is_associated_with::mitochondrial fusion by regulating is_associated_with::OPA1 activity. Its inhibition of the cleavage of OPA1 preserves mitochondrial is_associated_with::membrane potential, protects against is_associated_with::apoptosis, and maintains ATP levels. Its role in mitochondrial fusion also influences downstream processes such as mtDNA synthesis, cell growth, and is_associated_with::cristae organization. In addition, HIGD1A helps preserve mitochondrial function by regulating mitochondrial γ-secretase activity under hypoxic conditions. In the absence of HIGD1A, γ-secretase contributes to the accumulation of is_associated_with::amyloid beta in the mitochondria, leading to increased ROS production, mitochondrial dysfunction, and eventually, cell death. While HIGD1A predominantly contributes to cell survival, it can also promote apoptosis in neurons during the early developmental stages of the is_associated_with::central nervous system.

Clinical significance
Since HIGD1A promotes cell survival under hypoxia, the protein protects organs like the heart and brain from hypoxia-related diseases. In particular, HIGD1A localization to the nucleus correlates with the severity of stress in ischemic heart disease, hypoxic-ischemic is_associated_with::encephalopathy, and cancer, and thus may serve as a biomarker for these diseases. Moreover, HIGD1A is involved in inflammatory diseases, such as is_associated_with::atherosclerosis and is_associated_with::rheumatoid arthritis, through its role in macrophage survival. 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.

Interactions
HIGD1A is known to interact with:
 * AIF,
 * γ-secretase and
 * is_associated_with::OPA1.