Mitochondria: In Sickness and in Health

The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.

Recognition and Processing of Ubiquitin-Protein Conjugates by the Proteasome

Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelle's behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction.

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Mitochondrial form and function

Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance.

The Mitochondrial Basis of Aging

https://www.cell.com/developmental-cell/pdf/S1534-5807(07)00277-8.pdf

ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.

The Matrix Peptide Exporter HAF-1 Signals a Mitochondrial UPR by Activating the Transcription Factor ZC376.7 in C. elegans

Perturbation of the protein-folding environment in the mitochondrial matrix selectively upregulates the expression of nuclear genes encoding mitochondrial chaperones. To identify components of the signal transduction pathway(s) mediating this mitochondrial unfolded protein response (UPRmt), we first isolated a temperature-sensitive mutation (zc32) that conditionally activates the UPRmt in C. elegans and subsequently searched for suppressors by systematic inactivation of genes. RNAi of ubl-5, a gene encoding a ubiquitin-like protein, suppresses activation of the UPRmt markers hsp-60∷gfp and hsp-6∷gfp by the zc32 mutation and by other manipulations that promote mitochondrial protein misfolding. ubl-5 (RNAi) inhibits the induction of endogenous mitochondrial chaperone encoding genes hsp-60 and hsp-6 and compromises the ability of animals to cope with mitochondrial stress. Mitochondrial morphology and assembly of multi-subunit mitochondrial complexes of biotinylated proteins are also perturbed in ubl-5(RNAi) worms, indicating that UBL-5 also counteracts physiological levels of mitochondrial stress. Induction of mitochondrial stress promotes accumulation of GFP-tagged UBL-5 in nuclei of transgenic worms, suggesting that UBL-5 effects a nuclear step required for mounting a response to the threat of mitochondrial protein misfolding.

https://www.genetics.org/content/genetics/174/1/229.full.pdf

Ubiquitin-Like Protein 5 Positively Regulates Chaperone Gene Expression in the Mitochondrial Unfolded Protein Response

Oxidative protein folding by an endoplasmic reticulum localized peroxiredoxin

The burden of protein misfolding is believed to contribute to aging. However, the links between adaptations to conditions associated with protein misfolding and resistance to the time-dependent attrition of cellular function remain poorly understood. We report that worms lacking aip-1, a homologue of mammalian AIRAP (arsenic-inducible proteasomal 19S regulatory particle-associated protein), are not only impaired in their ability to resist exposure to arsenite but also exhibit shortened lifespan and hypersensitivity to misfolding-prone proteins under normal laboratory conditions. Mammals have a second, constitutively expressed AIRAP-like gene (AIRAPL) that also encodes a proteasome-interacting protein, which shares with AIRAP the property of enhancing peptide accessibility to the proteasome's active site. Genetic rescue experiments suggest that features common to the constitutively expressed worm AIP-1 and mammalian AIRAPL (but missing in the smaller, arsenite-inducible AIRAP) are important to lifespan extension. In worms, a single AIRAP-related protein links proteasomal adaptation to environmental stress with resistance to both proteotoxic insults and maintenance of animal life span under normal conditions.

https://www.pnas.org/content/pnas/105/19/7094.full.pdf

Yun Yang

Papers

ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.

The Matrix Peptide Exporter HAF-1 Signals a Mitochondrial UPR by Activating the Transcription Factor ZC376.7 in C. elegans

Ubiquitin-Like Protein 5 Positively Regulates Chaperone Gene Expression in the Mitochondrial Unfolded Protein Response

Oxidative protein folding by an endoplasmic reticulum localized peroxiredoxin

Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans.