SLC25A4

SLC25A4 is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix int

Solute Carrier Family 25 Member 4

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).
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).
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).

Biological Process adaptive thermogenesisISS:UniProtKB
Biological Process ADP transportManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process apoptotic mitochondrial changesIEA:Ensembl
Biological Process generation of precursor metabolites and energyManual Assertion Based On ExperimentTAS:ProtInc
Biological Process mitochondrial ADP transmembrane transportManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process mitochondrial ATP transmembrane transportManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process mitochondrial genome maintenanceManual Assertion Based On ExperimentTAS:ProtInc
Biological Process negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Biological Process negative regulation of necroptotic processManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of mitophagyISS:UniProtKB
Biological Process regulation of mitochondrial membrane permeabilityISS:UniProtKB

Mitochondrion inner membrane
Membrane
The complex formed with ARL2BP, ARL2 and SLC25A4/ANT1 is expressed in mitochondria (By similarity).
May localize to non-mitochondrial membranes (PubMed:27641616).

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.
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.
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.

Mitochondrial intermembrane: 1-7
Helical: 8-37
Mitochondrial matrix: 38-74
Helical: 75-99
Mitochondrial intermembrane: 100-109
Helical: 110-130
Mitochondrial matrix: 131-178
Helical: 179-199
Mitochondrial intermembrane: 200-210
Helical: 211-231
Mitochondrial matrix: 232-273
Helical: 274-291
Mitochondrial intermembrane: 292-298

Under cell death induction, transglutaminated by TGM2. Transglutamination leads to formation of covalent cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming polymers.