Recombinant Human ADP/ATP translocase 1 (SLC25A4) Protein

Function

ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). Substrate exchange across the membrane occurs consecutively with one substrate being transported first, then dissociating from the substrate binding site before the second substrate binds for transport in the opposite direction (PubMed:37278158). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (PubMed:31883789). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (By similarity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it (By similarity). Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:31883789). It is however unclear if SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates it (By similarity). Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity)

Subcellular Location

Mitochondrion inner membrane (Multi-pass membrane protein); Membrane (Multi-pass membrane protein)

Disease Association

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2 (PEOA2) : A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. [The disease is caused by variants affecting the gene represented in this entry] | Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type (MTDPS12B) : An autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and accumulation of abnormal mitochondria. [The disease is caused by variants affecting the gene represented in this entry] | Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type (MTDPS12A) : An autosomal dominant mitochondrial disorder characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Expressed in erythrocytes (at protein level)

Subunit

(Microbial infection) Interacts with HIV-1 Vpr

• Neckelmann N. et al. cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. — Proc. Natl. Acad. Sci. U.S.A. (1987)
• Cozens A.L. et al. DNA sequences of two expressed nuclear genes for human mitochondrial ADP/ATP translocase. — J. Mol. Biol. (1989)
• Li K. et al. A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed. — J. Biol. Chem. (1989)
• Wang W. et al. Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing. — Nucleic Acids Res. (2011)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Houldsworth J. et al. Two distinct genes for ADP/ATP translocase are expressed at the mRNA level in adult human liver. — Proc. Natl. Acad. Sci. U.S.A. (1988)
• Bienvenut W.V. et al. PubMed: CI-590F7T6PAE2U (OCT-)