AIFM1

AIFM1 Background

The AIFM1 gene encodes a flavoprotein, apoptosis-inducing factor, mitochondrion-associated 1(AIFM1), which is involved in apoptosis, mitochondrial function, ROS production and neurodegeneration ^[1]. AIFM1 is found in the mitochondrial intermembrane space in healthy cells. As an NADH oxidase with a local redox function, AIFM1 is essential for optimal oxidative phosphorylation and efficient antioxidant defense ^[2]. Lack of AIFM1 leads to neurodegeneration, skeleton muscle atrophy, and dilated cardiomyopathy ^[2]. In response to apoptotic stimuli, AIFM1 is released from mitochondria and translocates to the nucleus, where it triggers chromatin condensation and large-scale DNA degradation in a caspase-independent manner. Both of these are nuclear features of apoptosis. Besides, AIFM1 induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9 ^[3]. The nuclear localization of AIFM1 can be inhibited by blocking upstream signals of apoptosis. Evidence suggests that the redox-active enzymatic region of AIFM1 may be antiapoptotic while the DNA binding region is proapoptotic ^[4]. Zong et al. found that the AIFM1 gene ubiquitously expressed in the mouse inner ear, especially in the cytoplasm of inner ＆ outer hair cells and spiral ganglion neurons, which is consistent with its role in normal auditory function ^[5]. Mutations in the AIFM1 gene cause combined oxidative phosphorylation deficiency 6 (COXPD6) ^[6], severe mitochondrial encephalomyopathy. Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4) is also associated with AIFM1 mutations ^[7]. This disorder results in neuropathy and axonal ＆ motor-sensory defects, accompanied by deafness and cognitive disability.

[1] Polster BM. AIF, reactive oxygen species, and neurodegeneration: a "complex" problem [J]. Neurochem Int 2013; 62: 695-702.
[2] Modjtahedi N., Giordanetto F., et al. Apoptosis-inducing factor: Vital and lethal [J]. Trends Cell Biol. 2006; 16: 264-272.
[3] Granville DJ, Cassidy BA, et al. Mitochondrial release of apoptosis-inducing factor and cytochrome c during smooth muscle cell apoptosis [J]. Am J Pathol. 2001 Jul;159(1):305-11.
[4] Lipton SA, Bossy-Wetzel E. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity [J]. Cell. 2002 Oct 18;111(2):147-50.
[5] Zong, L., Guan, J., et al. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder [J]. J. Med. Genet. 2015, 52: 523-531.
[6] Kettwig M, Schubach M, et al. From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1 [J]. Mitochondrion 2015; 21C: 12-8.
[7] Rinaldi C, Grunseich C, et al. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor [J]. Am J Hum Genet 2012; 91: 1095-1102.