Artificial Hsp104-mediated systems for re-localizing protein aggregates.

Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to control their toxicity. To approach the role of sPQC in cellular fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in budding yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrate that aggregates of mutant huntingtin (mHtt), the disease-causing agent of Huntington's disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. We find that the artificial removal of mHtt inclusions from mother cells protects them from cell death suggesting that even large mHtt inclusions may be cytotoxic, a trait that has been widely debated. In contrast, removing inclusions of endogenous age-associated misfolded proteins does not significantly affect the lifespan of mother cells. We demonstrate also that this approach is able to manipulate mHtt inclusion formation in human cells and has the potential to be useful as an alternative, complementary approach to study the role of sPQC, for example in aging and neurodegenerative disease.

A tale of two pathways: Regulation of proteostasis by UPRmt and MDPs.

Mitochondrial fitness is critical to organismal health and its impairment is associated with aging and age-related diseases. As such, numerous quality control mechanisms exist to preserve mitochondrial stability, including the unfolded protein response of the mitochondria (UPRmt). The UPRmt is a conserved mechanism that drives the transcriptional activation of mitochondrial chaperones, proteases, autophagy (mitophagy), and metabolism to promote restoration of mitochondrial function under stress conditions. UPRmt has direct ramifications in aging, and its activation is often ascribed to improve health whereas its dysfunction tends to correlate with disease. This review pairs a description of the most recent findings within the field of UPRmt with a more poorly understood field: mitochondria-derived peptides (MDPs). Similar to UPRmt, MDPs are microproteins derived from the mitochondria that can impact organismal health and longevity. We then highlight a tantalizing interconnection between UPRmt and MDPs wherein both mechanisms may be efficiently coordinated to maintain organismal health.