Abstract
Mitochondrial nucleoids consist of several different groups of proteins, many of which are involved in essential cellular processes such as the replication, repair and transcription of the mitochondrial genome. The eukaryotic, ATP-dependent protease Lon is found within the central nucleoid region, though little is presently known about its role there. Aside from its association with mitochondrial nucleoids, human Lon also specifically interacts with RNA. Recently, Lon was shown to regulate TFAM, the most abundant mtDNA structural factor in human mitochondria. To determine whether Lon also regulates other mitochondrial nucleoid- or ribosome-associated proteins, we examined the in vitro digestion profiles of the Saccharomyces cerevisiae TFAM functional homologue Abf2, the yeast mtDNA maintenance protein Mgm101, and two human mitochondrial proteins, Twinkle helicase and the large ribosomal subunit protein MrpL32. Degradation of Mgm101 was also verified in vivo in yeast mitochondria. These experiments revealed that all four proteins are actively degraded by Lon, but that three of them are protected from it when bound to a nucleic acid; the Twinkle helicase is not. Such a regulatory mechanism might facilitate dynamic changes to the mitochondrial nucleoid, which are crucial for conducting mitochondrial functions and maintaining mitochondrial homeostasis.
Highlights
Mitochondria are some of the most important organelles of eukaryotic cells
We found that all of these proteins could serve as Lon substrates, suggesting that the mitochondrial Lon protease could be involved in the regulation of such fundamental processes as nucleoid packaging, mitochondrial DNA (mtDNA) replication, mtDNA maintenance and recombination, and the assembly of mitochondrial ribosomes
We examined the ability of the ATP-dependent mitochondrial matrix protein Lon to degrade four mitochondrial proteins involved in, or expected to be involved in, mtDNA packaging (Abf2) and recombination (Mgm101) in yeast and mtDNA replication (Twinkle) and translation (MrpL32) in humans
Summary
Mitochondria are some of the most important organelles of eukaryotic cells. Their proper function depends on both nuclear and mitochondrial DNA, whose coordinated regulation of transcription and translation is crucial for cellular survival[1]. The mitochondrial Lon protease itself has been identified as an integral nucleoid core factor in human mitochondria[11], it is involved in selective protein turnover (including ribosomal proteins)[12] and the ATP-dependent degradation of misfolded or damaged mitochondrial proteins[13, 14] It has a chaperone-like function in the assembly of certain mitochondrial complexes, which persists even if its proteolytic activity is impaired[15]. We evaluate the potential of proteins known or expected to be involved in mtDNA packaging, replication, repair, and recombination to be substrates for the mitochondrial Lon protease Both human and yeast proteins were assessed to determine how general Lon’s influence is likely to be across even quite unrelated eukaryotic species. Some forms of the yeast mtDNA-binding protein Mgm[101] have been shown to carry out the Rad[52] DNA recombination activities of strand annealing and D-loop formation[27, 28], while human MrpL32, a component of the 39S large subunit of the mitochondrial ribosome, is known to be important for proper ribosome assembly and, the proper synthesis and assembly of the mtDNA-encoded components of the oxidative phosphorylation respiratory complex[29]
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