Caenorhabditis elegans as a model system to study intercompartmental proteostasis: Interrelation of mitochondrial function, longevity, and neurodegenerative diseases

Abstract

The protein quality control system, composed of molecular chaperones and proteases, is of vital importance for the maintenance and function of the proteome and the health of the cell. To achieve this, the cellular proteostasis network integrates the protein folding machinery across all compartments of the eukaryotic cell to enable efficient communication and coordinate a rapid response of folding capacity. Quality control in the mitochondria, however, differs from its cytosolic counterpart due to its prokaryotic origin, and is entirely encoded by the nuclear genome. The control and regulatory cross-talk of mitochondrial function in cellular proteostasis is essential for cellular metabolism, organismal development, and lifespan. Consequently, mitochondrial dysfunction has dramatic effects on the development and progression of a number of neurodegenerative diseases, such as Friedreich's ataxia and Parkinson's disease. Studies using Caenorhabditis elegans as a model system have greatly contributed to our current knowledge of inter-compartmental proteostasis on the cellular and organismal levels.

Fig. 1

Balancing the cellular proteostasis by compartment-specific unfolded protein response (UPR). This cartoon depicts the integration of the organellar UPR’s into the cellular proteostasis network. The cellular proteostasis is a balance of the folding load of all organelles and their respective response mechanisms (UPR). Perturbance of the client to chaperone ratio, e.g., due to proteotoxic stress, could result in an imbalance of the cellular proteostasis. To rebalance the proteostasis, the cell can activate organelle-specific UPR’s to cope with the excess of client proteins.

Fig. 2

C. elegans polyglutamine model. A: Expression of polyQ in the body wall muscle (P_unc-54Q(n)::YFP; top) and throughout the nervous system (P_F25B3.3Q(n)::CFP; bottom). The expression of both models shows a polyQ length-dependent aggregation pattern. B: FRAP analysis of poly- Q::YFP in body wall muscle cells to analyze solubility of polyQ proteins. Images are taken before bleaching (pre-bleach, left), immediately after bleaching (post-bleach, middle), and after a recovery period (recovery, right). Q0::YFP recovers rapidly and is soluble, whereas Q40::YFP foci do not recover and are immobile. C: Quantification of FRAP results. The graphs show the relative fluorescence intensity (RFI) for each time point (Brignull et al., 2006b).

Fig. 3

Model of the mitochondrial unfolded protein response (UPR^mt) in C. elegans. Proteotoxic stress triggers a response of ClpXP, whose proteolytic activity is required to transmit the signal to the cytoplasm presumably via peptide translocation by HAF-1. Here, the transcription factors, UBL-5 and DVE-1, which form a complex, and ZC376.7 redistribute to the nucleus. DVE-1 binds to the promoter region of the mitochondrial chaperone genes, hsp-6 and hsp-60. The expression of ubl-5 is also up-regulated and probably acts as a feed-forward regulation to enhance the signal. This activation of the UPR^mt results in an accumulation of HSP-6 (mt Hsp70) and HSP-60 (mt chaperonin) in the mitochondria. RHEB is thought to act as a suppressor of the UPR^mt, probably with cessation of the stress conditions. Open questions of the regulation of the UPR^mt are indicated with question marks and are further discussed in the text.