Alternative titles; symbols
HGNC Approved Gene Symbol: AFG1L
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:108,295,054-108,526,001 (from NCBI)
AFG1L is a mitochondrial ATPase that mediates degradation of nuclear-encoded components of electron transport chain complex IV and is required for normal mitochondrial morphology (Cesnekova et al., 2016).
By genomic sequence analysis, Abrahams et al. (2002) identified human AFG1L, which they called LACE1. LACE1 orthologs are present in human, mouse, pufferfish, fly, yeast, and bacteria. The deduced 55-kD human protein has an ATP/GTP-binding P-loop and a 5-domain structure. RT-PCR analysis showed Lace1 expression in all mouse tissues tested, with highest expression in heart, kidney, and lactating breast. Expression was lower in virgin, pregnant, and involuting breast. A variant lacking exon 3 was expressed at low levels in most mouse tissues, but it was upregulated during embryonic development and was expressed at a level comparable to the full-length transcript in adult brain.
Using mitochondrial subfractionation of HEK293 cells followed by immunoblot analysis, Cesnekova et al. (2016) found that endogenous LACE1 was an integral mitochondrial membrane protein with an apparent molecular mass of about 50 kD. Western blot analyses showed that LACE1 existed in complexes of about 140, 400, and 500 kD.
By mutation analysis in transfected HEK293 cells, Cesnekova et al. (2016) showed that the P-loop was required for LACE1 protein processing and targeting to mitochondria. Electron microscopy of LACE1-knockdown cells showed fragmented mitochondrial reticulum and altered mitochondrial shape and cristae morphology. OPA1 (605290), a GTPase that regulates mitochondrial fusion, was dysregulated in the absence of LACE1. LACE1-knockdown cells also showed higher levels of nuclear-encoded components of complex IV, namely COX4 (see 123864), COX5A (603773), and COX6A (see 602072), whereas mitochondrial-encoded components of complex IV and subunits of other respiratory chain complexes were unaffected. Accumulation of COX4, COX5A, and COX6A in mitochondria was abrogated by reintroducing wildtype, but not LACE1 mutants deficient in ATP binding or hydrolysis, into the LACE1-knockdown cells. Spectrophotometric analysis showed reduced activity of complexes III and IV and increased activity of complex II in LACE1-knockdown cells compared with controls, despite a normal level of complex III and only mildly elevated levels of complexes II and IV. Western blot analysis also showed decreased expression of LONP1 (605490) protease and increased expression of YME1L1 (607472) inner membrane protease in mitochondria of LACE1-knockdown cells. Using affinity purification, the authors showed that YME1L1, COX4, and COX5a copurified with LACE1. Cesnekova et al. (2016) concluded that LACE1 plays a crucial role in mitochondrial protein homeostasis.
Abrahams et al. (2002) determined that the AFG1L gene contains 13 exons and spans about 228 kb. Both human and mouse AFG1L genes have conserved estrogen receptor (ESR1; 133430)-binding sites within 2.5 kb of the first exon.
By genomic sequence analysis, Abrahams et al. (2002) mapped the AFG1L gene to chromosome 6.
Gross (2017) mapped the AFG1L gene to chromosome 6q21 based on an alignment of the AFG1L sequence (GenBank AF520418) with the genomic sequence (GRCh38).
Abrahams, B. S., Mak, G. M., Berry, M. L., Palmquist, D. L., Saionz, J. R., Tay, A., Tan, Y. H., Brenner, S., Simpson, E. M., Venkatesh, B. Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci. Genomics 80: 45-53, 2002. [PubMed: 12079282] [Full Text: https://doi.org/10.1006/geno.2002.6795]
Cesnekova, J., Rodinova, M., Hansikova, H., Houstek, J., Zeman, J., Stiburek, L. The mammalian homologue of yeast Afg1 ATPase (lactation elevated 1) mediates degradation of nuclear-encoded complex IV subunits. Biochem. J. 473: 797-804, 2016. [PubMed: 26759378] [Full Text: https://doi.org/10.1042/BJ20151029]
Gross, M. B. Personal Communication. Baltimore, Md. 4/28/2017.