Mitochondrial Disorders Associated with the Mitochondrial DNA Polymerase g: A Focus on Intersubunit Interactions

Abstract

The mitochondrion contains only one DNA polymerase, DNA polymerase gamma (pol γ), to repair and replicate the mitochondrial genome. Human pol γ is a heterotrimer consisting of a 140 kDa catalytic subunit, p140, and a ~ 110 kDa homodimeric accessory subunit, p552. The catalytic p140 subunit harbors DNA polymerase, 5′-deoxyribose phosphate lyase, and 3′-5′ exonuclease activities while the accessory subunit confers processivity to the holoenzyme. The nuclear POLG gene encodes p140 while the nuclear POLG2 gene encodes p552. Mitochondrial diseases associated with mutations in these genes, POLG- and POLG2-related disorders, are composed of early-childhood-onset diseases and late-adulthood-onset diseases. For over a decade, POLG-related diseases have been intensively studied and include Alpers–Huttenlocher syndrome (AHS), Childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), autosomal recessive progressive external ophthalmoplegia (arPEO), and autosomal-dominant progressive external ophthalmoplegia (adPEO). In this chapter, we review recently identified POLG2 mutations associated with mitochondrial disease as well as key POLG mutations that encode variants that disrupt the interface between p140 and p552. In the absence of POLG2 family genetics, we discuss enzymatic deficiencies of protein variants, amino acid residue conservation, clinical evidence as well as other indicators of mutation pathogenicity. Recent biochemical studies suggests that p552 contributes to balancing p140 DNA polymerase and exonuclease activities and disruption of this balance may contribute to mitochondrial DNA (mtDNA) depletion in vivo. Classifying mutations as either pathogenic or neutral is further challenged by syntenic and compound heterozygous mutations and emphasizes the importance of understanding family genetics and biochemically characterizing p140 and p552 variants.