Polg2 is essential for mammalian embryogenesis and is required for mtDNA maintenance

Abstract

Mammalian mitochondrial DNA (mtDNA) is replicated by the heterotrimeric Pol γ comprised of a single catalytic subunit, encoded by Polg, and a homodimeric accessory subunit encoded by the Polg2 gene. While the catalytic subunit has been shown to be essential for embryo development, genetic data regarding the accessory subunit are lacking in mammalian systems. Here, we describe the generation of heterozygous (Polg2(+/-)) and homozygous (Polg2(-/-)) knockout (KO) mice. Polg2(+/-) mice are haplosufficient and develop normally with no discernable difference in mitochondrial function through 2 years of age. In contrast, the Polg2(-/-) is embryonic lethal at day 8.0-8.5 p.c. with concomitant loss of mtDNA and mtDNA gene products. Electron microscopy shows severe ultra-structural defects and loss of organized cristae in mitochondria of the Polg2(-/-) embryos as well as an increase in lipid accumulation compared with both wild-type (WT) and Polg2(+/-) embryos. Our data indicate that Polg2 function is critical to mammalian embryogenesis and mtDNA replication, and that a single copy of Polg2 is sufficient to sustain life.

Maintenance and Expression of Mammalian Mitochondrial DNA

“…At the core of mtDNA replication is DNA polymerase-γ (POLγ), the only replicative polymerase in mitochondria. Human POLγ is a heterotrimer, with one catalytic subunit (POLγA) and two accessory subunits (POLγB) (78-80); mouse knockouts lacking either POLγA or POLγB are lethal to the embryo (81,82). A second DNA polymerase, referred to as PrimPol (primase polymerase), has been reported to act in both the nucleus and in mitochondria.…”

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation

“…For example, genetic mutations that decrease or disrupt OXPHOS often result in heart failure and embryonic lethality (29,34,35). Furthermore, mutations that disrupt mitochondrial structure and function have also interfered with cardiomyocyte differentiation and development (11,12,18,58), and many of these have ultimately succumbed to heart failure and embryonic lethality.…”

Mitochondrial dysfunction and ovarian aging

“…30 Several reports based on the use of transgenic methods have revealed a key role for specific genes in mitochondrial diseases. [31][32][33][34][35][36] Regulation of mtDNA gene expression is extremely important for modulating the OXPHOS capacity in response to metabolic requirements and in stress conditions.…”

“…All the components involved in mtDNA replication and transcription are encoded in the nuclear genome, and mutations of genes essential for mtDNA replication (POLγ and TWINKLE) and for transcription/translation (TFAM, TFB1M, mTERFs, POLRMT, LRPPRC, and DARS2) are all embryonic lethal except mTERF1. [34][35][36][38][39][40][41][42][43][44] Mitochondria are dynamic organelles that are constantly undergoing fusion and fission to adapt to cellular energetic demands and maintain the mitochondrial function. A number of proteins belonging to the dynamin GTPase protein family are involved in mitochondrial fission and fusion.…”