The Liu lab has broad interests in exploring the molecular mechanisms that govern the maintenance of cellular homeostasis. Currently, we focus on two major directions: mitochondrial stress response and nutrient sensing mechanisms.
Mitochondrial Stress Response
Proper maintenance of mitochondrial function is crucial for the survival of organisms. Organisms evolved stress response pathways to survey mitochondrial function and activate repair programs upon mitochondrial stress. Failure to sense or repair damaged mitochondria has been implicated in aging and numerous diseases such as cardiac dysfunction and neurodegenerative disorders. The goal of our research program is to combine the power of worm genetics and biochemistry, to understand and manipulate mitochondrial stress response pathways to promote the healthy survival of organisms. We focus on three aspects of mitochondrial studies:
1. Molecular mechanism of mitochondria stress response pathway
Mitochondria bear a trace of their bacterial origin but are almost entirely composed of proteins encoded by the nuclear genome. The function of the mitochondrion is subject to mitochondrial unfolded protein response (UPRmt) pathways that monitor and coordinate mitochondrial function to adjust the expression and assembly of mitochondrial components. Once activated, UPRmt not only upregulates mitochondrial protective proteins such as chaperones and proteases, but also resets metabolic state through the regulation of genes involved in glycolysis and oxidative phosphorylation. We have finished a genome-wide RNAi screen to derive strains of C. elegans that are “blind” to mitochondrial dysfunction, and therefore did not induce UPRmt. The initial analysis of the screen hits allowed us to demonstrate the important functions of the mevalonate and ceramide signaling in mitochondrial surveillance. Currently, we are carrying out in-depth studies of other hits from our initial screen. (Liu et al., Nature 2014)
2. Cell-non-autonomous activation of mitochondrial stress response
To cope with a challenging and unpredictable environment, living systems have evolved several organelle-specific stress responses, such as mitochondrial unfolded protein response (UPRmt). In C. elegans, activation of UPRmt alters the organismal investment strategy to delay reproduction and development, and extend lifespan. These physiological changes must coordinate multiple tissues and organs. The decision to shift the resource allocation strategy in C. elegans seems to be sensed and coordinated by the nervous system. Inhibition of mitochondrial function only in neurons induced the expression of mitochondrial chaperones in distal tissues and caused a lifespan extension, suggesting a cell non-autonomous regulation of mitochondrial stress response. Using a tissue-specific CRISPR/Cas9 system, we found that neuropeptide FLP-2 plays essential roles in cell-non-autonomous activation of UPRmt. (Shao et al., Cell Research 2016)
3. Transgenerational inheritance of mitochondrial stress adaptation
Exposure of C. elegans to mitochondrial inhibitors or RNAi of nuclear encoded mitochondrial genes at the parental generation makes their descendants stress-adaptive. More importantly, exposure of worms to a natural mitochondrial challenge, a Pseudomonas strain from habitat harboring wild C. elegans populations, also induced stress resistance, suggesting that inheritance of mitochondrial stress adaptation would benefit the species for their survival. Further mechanistic studies reveal that mitochondrial stress induces epigenetic changes, which persist over several generations on the promoters of mitochondrial unfolded protein response (UPRmt) genes. How these epigenetic marks are established and erased over generations is under extensive analysis in the lab.
Nutrient Sensing Mechanisms
Nutrient availability greatly affects organisms’ reproduction, lifespan and survival. Combining the power of worm genetics, cell biology and biochemistry, we are actively exploring molecular mechanisms that enable organisms to sense nutrient availability.