Protein turnover is considered as an important mechanism to avoid the accumulation of molecular damage, a major hallmark of aging [1]. A first proteostasis system we study is mitochondrial homeostasis which appears to be maintained by mitophagy [2]. To test whether mitochondrial turnover is an important determinant of longevity, we optimized a new technique which involves a mitochondrially targeted photoswitchable protein DENDRA2 to study mitochondrial autophagy in long-lived daf 2
(e1370)III mutants. Our results suggest that the turnover of photoconverted DENDRA2 is reduced in
daf-2(
e1370)III mutants compared to control worms. However, the mechanism responsible for the degradation of converted DENDRA2 in our transgene worms is not yet known. Besides mitophagy, the mitochondrial proteases may be important in mitochondrial quality control. A second system we investigate is protein aggregation clearance. MALT1 (mucosa-associated lymphoid tissue), a human paracaspase, is known as a positive regulator of the inflammatory transcription factor NF-kB in lymphocytes [3]. Recently, loss of MALT1 in mouse fibroblasts and neuronal cells was found to result in the accumulation of damaged mitochondria and protein aggregates, suggesting an unexpected function of MALT1 in autophagosomal degradation. We currently investigate the role of F22D3.6 (MALT1 homolog) in protein aggregate clearance in C. elegans. First results show that neuronal-specific RNAi inactivation of F22D3.6 caused a subtle lifespan shortening. We are exploring the effect of F22D3.6 knockdown on protein aggregates by the use of FRAP experiments in transgene worms in which fluorescently tagged aggregation-prone polyglutamine (polyQ) proteins are expressed throughout the nervous system. Preliminary results suggest a conserved role of the MALT1 homolog F22D3.6 in protein aggregation clearance. [1] Levine RL , Stadtman ER (2001) [2] Lemasters JJ (2005) [3] Staal J, Bekaert T , Beyaert R (2011).