Abstract
Mitochondrial dysfunction is a frequent participant in common diseases and a principal suspect in aging. To combat mitochondrial dysfunction, eukaryotes have evolved a large repertoire of quality control mechanisms. One such mechanism involves the selective degradation of damaged or misfolded mitochondrial proteins by mitochondrial resident proteases, including proteases of the ATPase Associated with diverse cellular Activities (AAA+) family. The importance of the AAA+ family of mitochondrial proteases is exemplified by the fact that mutations that impair their functions cause a variety of human diseases, yet our knowledge of the cellular responses to their inactivation is limited. To address this matter, we created and characterized flies with complete or partial inactivation of the Drosophila matrix-localized AAA+ protease Lon. We found that a Lon null allele confers early larval lethality and that severely reducing Lon expression using RNAi results in shortened lifespan, locomotor impairment, and respiratory defects specific to respiratory chain complexes that contain mitochondrially encoded subunits. The respiratory chain defects of Lon knockdown (LonKD) flies appeared to result from severely reduced translation of mitochondrially encoded genes. This translational defect was not a consequence of reduced mitochondrial transcription, as evidenced by the fact that mitochondrial transcripts were elevated in abundance in LonKD flies. Rather, the translational defect of LonKD flies appeared to be derived from sequestration of mitochondrially encoded transcripts in highly dense ribonucleoparticles. The translational defect of LonKD flies was also accompanied by a substantial increase in unfolded mitochondrial proteins. Together, our findings suggest that the accumulation of unfolded mitochondrial proteins triggers a stress response that culminates in the inhibition of mitochondrial translation. Our work provides a foundation to explore the underlying molecular mechanisms.
Highlights
Mitochondria are responsible for most of the energy produced by a cell, but the generation of reactive oxygen species (ROS) as a byproduct of this activity can damage mitochondrial proteins, lipids, and DNA1–3
We know little of the cellular responses and the pathogenic mechanisms of diseases caused by mutations in the genes that encode the AAA+ proteases
Our current work advances our understanding of these matters by showing that inactivation of the AAA+ protease Lon results in respiratory chain defects that appear to result from translational inhibition
Summary
Mitochondria are responsible for most of the energy produced by a cell, but the generation of reactive oxygen species (ROS) as a byproduct of this activity can damage mitochondrial proteins, lipids, and DNA1–3. Few Lon substrates are known with certainty, a number of candidate Lon substrates have been identified from biochemical studies aimed at the identification of Lon-binding proteins, including the mitochondrial DNA (mtDNA) replication factors Twinkle, polymerase gamma, Tfam, and the chaperones Hsp[60] and mtHsp7013–19. Subsequent studies aimed at validating the significance of these binding interactions indicated that Lon inactivation results in increased mtDNA copy number and destabilization of Hsp[60] and mtHsp[70] under environmental stress[20,21,22]. It is unclear whether these findings reflect direct effects of Lon inactivation, or downstream cellular responses to loss of Lon activity. Mutations in Lon have been shown to result in the recessive developmental disorder CODAS (cerebral, ocular, dental, auricular, and skeletal) syndrome, yet the mechanisms by which mutations in Lon cause this disease are currently unknown[23]
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