Mutations in SUCLA2: a tandem ride back to the Krebs cycle

Abstract

Mitochondria are small membrane-bound intracellular organelles that are the principal source of adenosine triphosphate (ATP), the high-energy phosphate molecule required by all human cells. ATP is produced by the mitochondrial respiratory chain which is linked to oxidative phosphorylation. Thirteen essential respiratory chain polypeptides are synthesized from small circles of DNA present within each mitochondrion (the mitochondrial genome, mtDNA). Qualitative defects of mtDNA are a major cause of human disease: both point mutations and deletions of mtDNA cause a biochemical defect which often affects skeletal muscle and the nervous system, presenting with neurological features (Zeviani and Di Donato, 2004). MtDNA is inherited exclusively down the maternal line, and pathogenic mtDNA mutations are either maternally inherited or sporadic, affecting at least 1 in 5000 (Schaefer et al ., 2004). More recently, autosomal recessive mitochondrial disorders have gained increasing prominence (Table 1). Mutations have been described in nuclear genes coding for respiratory chain proteins or assembly factors, and nuclear-encoded intra-mitochondrial translation factors have recently entered the lime-light (Coenen et al ., 2004; Valente et al ., 2007). However, a new class of genetic disease has emerged as an important cause of human pathology, ranking along-side the primary mtDNA mutations in terms of their frequency. These diseases are also due to nuclear gene mutations, and all affect proteins that maintain a healthy mitochondrial genome. View this table: Table 1 Nuclear genes causing mitochondrial disease Genetic linkage in families with autosomal dominant chronic progressive external ophthalmoplegia (ad-PEO) led the way to pathogenic mutations in three nuclear genes: POLG which codes for the intra-mitochondrial DNA polymerase (pol γ), PEO1 which codes for the mtDNA helicase Twinkle, and SLC25A4 which codes for the adenine nucleotide translocase ANT1 (Kaukonen et al ., 1996; Spelbrink et al ., 2001; Van Goethem et al ., 2001). Subsequent candidate gene sequencing identified …