Apoptosis-inducing factor 1, mitochondrial is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the ''AIFM1''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

on the X chromosome. This protein localizes to the mitochondria, as well as the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

, where it carries out nuclear fragmentation as part of

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyst ...

-independent apoptosis.

Structure

AIFM1 is expressed as a 613- residue precursor protein that containing a mitochondrial targeting sequence (MTS) at its

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and two nuclear leading sequences (NLS). Once imported into the mitochondria, the first 54 residues of the N-terminal are cleaved to produce the mature protein, which inserts into the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...

. The mature protein incorporates the

FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...

cofactor and folds into three structural domains: the FAD-binding domain, the NAD-binding domain, and the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

. While the C-terminal is responsible for the proapoptotic activity of AIFM1, the FAD-binding and NAD-binding domains share the classical Rossmann topology with other flavoproteins and the NAD(P)H dependent reductase activity. Three alternative transcripts encoding different

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

s have been identified for this gene. Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains. A pseudogene that is thought to be related to this gene has been identified on chromosome 10.

Function

This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells that is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the cleavage of this protein at residue 102 by

calpain A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA ...

s and/or

cathepsin Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases ( enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are d ...

s into a soluble and proapoptogenic form that translocates to the nucleus, where it effects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. AIFM1 also contributes reductase activity in

redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...

metabolism.

Clinical significance

Mutations in the AIFM1

are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome). At a cellular level, AIFM1 mutations result in deficiencies in

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

, leading to severe mitochondrial encephalomyopathy. Clinical manifestations of this mutation are characterized by

muscular atrophy Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weaknes ...

, neuropathy,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...

, psychomotor regression, hearing loss and seizures.

Interactions

AIFM1 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...

with

HSPA1A Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the ''HSPA1A'' gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and mis ...

Evolution

Phylogenetic analysis indicates that the divergence of the AIFM1 and other human AIFs (AIFM2a and AIFM3) sequences occurred before the divergence of eukaryotes. This conclusion is supported by domain architecture of these proteins. Both eukaryotic and eubacterial AIFM1 proteins contain additional domain AIF_C.

References

External links

AIFM1
on the Atlas of Genetics and Oncology * {{PDB Gallery, geneid=9131 Proteins