LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs

Abstract

Regulation of mtDNA expression is critical for maintaining cellular energy homeostasis and may, in principle, occur at many different levels. The leucine-rich pentatricopeptide repeat containing (LRPPRC) protein regulates mitochondrial mRNA stability and an amino-acid substitution of this protein causes the French-Canadian type of Leigh syndrome (LSFC), a neurodegenerative disorder characterized by complex IV deficiency. We have generated conditional Lrpprc knockout mice and show here that the gene is essential for embryonic development. Tissue-specific disruption of Lrpprc in heart causes mitochondrial cardiomyopathy with drastic reduction in steady-state levels of most mitochondrial mRNAs. LRPPRC forms an RNA-dependent protein complex that is necessary for maintaining a pool of non-translated mRNAs in mammalian mitochondria. Loss of LRPPRC does not only decrease mRNA stability, but also leads to loss of mRNA polyadenylation and the appearance of aberrant mitochondrial translation. The translation pattern without the presence of LRPPRC is misregulated with excessive translation of some transcripts and no translation of others. Our findings point to the existence of an elaborate machinery that regulates mammalian mtDNA expression at the post-transcriptional level.

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

“…(43); (iii) methylcrotonyl-CoA carboxylase (MCCC) subunit ␣, which is an enzyme involved in leucine and isovaleric acid catabolism and is associated with a recessive genetic disorder termed MCCC-deficient syndrome (44,45); and (iv) leucinerich PPR-containing protein (LRPPRC), a protein involved in RNA translation and stability of mitochondrially encoded COX subunits, which are critical steps in the regulation of mitochondrial biogenesis (46,47). Because loss of endogenous LRPPRC is associated with aberrations in mitochondrial morphology and dysfunction in vivo (47), it is conceivable that mOGT-mediated O-GlcNAcylation of LRPPRC may be part of the mechanism by which mOGT siRNA transfection generates the observed abnormal phenotypes in mitochondrial content and morphology.…”

Pentatricopeptide repeats

“…44 The mammalian mitochondrial PPR protein, LRPPRC, which is important for polyadenylation and translation, forms an intimate complex with another RNA-binding protein, SLIRP, such that each protein requires the other for their stability. [69][70][71] Importantly, the editing PPR proteins of Arabidopsis must associate with multiple organelle RNA editing factor (MORF) family proteins or, in some cases, an autonomous DYW domain protein, DYW1, to deaminate their target RNA bases. [72][73][74][75] To date, a complete description of the proteins required for RNA editing has not been elucidated.…”

Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion

“…LRPPRC encodes a leucine-rich pentatricopeptide repeat containing protein that is targeted to the mitochondrial matrix (28). In the mitochondrial matrix, LRPPRC forms a ribonucleoprotein complex with the stem-loop RNA binding protein SLIRP and mitochondrial mRNAs (17,29). The LRPPRC/SLIRP complex activates the mitochondrial poly(A) polymerase MTPAP, and thereby promotes the polyadenylation of mitochondrial mRNAs (29,30).…”

“…In the mitochondrial matrix, LRPPRC forms a ribonucleoprotein complex with the stem-loop RNA binding protein SLIRP and mitochondrial mRNAs (17,29). The LRPPRC/SLIRP complex activates the mitochondrial poly(A) polymerase MTPAP, and thereby promotes the polyadenylation of mitochondrial mRNAs (29,30). LRPPRC/ SLIRP/MTPAP-dependent polyadenylation stabilizes mitochondrial mRNAs, such as COXI and COXII, which encode two subunits of complex IV (29,30).…”