Mitochondrial Protein Homeostasis in Stress and Aging

Mitochondria are a central hub of cellular metabolism and signaling, a crucial organelle whose dysfunction can cause disease and whose activity is intimately connected to aging. Studies in our lab focus on mitochondrial biology on two levels:

 

(i) Intra-cellular level: We aim to identify the pathways that protect mitochondria from internal and external insults. Recent work from our lab identified two histone demethylases that regulate the mitochondrial stress response (1). In another line of work, we found that the mitochondrial and cytosolic stress responses are coordinated by lipids (2). Currently, we aim to gain further mechanistic and regulatory insight into how these pathways support cellular protein homeostasis, and uncover novel interactions of mitochondrial stress responses with other organelles. 

 

ii) Inter-cellular level: Recent work from our lab showed that mitochondria within certain tissues actively signal to regulate the activity of mitochondria in other, distal, tissues (3-4). We have found that a tissue-specific mitochondrial stress can be sensed and transmitted to distal cells, invoking a cell non-autonomous mitochondrial stress response that extends life span. Further work from our lab implicated Wnt signaling in this communication (5). Currently, we are working towards understanding the specific cells that are able to signal mitochondrial stress to other tissues, and the functional and morphological consequences of its signaling. We are also investigating the preservation of this signaling system in mice, and the consequence on mammalian physiology and health.

 

Refs: 

(1) Merkwirth C, et al.

Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.  Cell. 2016 May 165, 1–15.  PMID: 27133168   pdf

(2) Kim, HE, et al

Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic. Stress Response.  Cell.  2016 Sept 8.  PMID: 27610574   pdf

(3) Durieux J, et al.

The cell-non-autonomous nature of electron transport chain-mediated longevity. 

Cell. 2011;144(1):79-91. PMID: 21215371   pdf

(4) Berendzen, KM, et al.

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis.  

Cell.  2016 Sept 8.  PMID: 26601575   pdf

(5) Zhang, Q, et al. 

The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.  

Cell.  2018 Aug 9.  PMID:  30057120   pdf

 

188 Li Ka Shing Center #430, Berkeley, CA 94720      (510) 664-4951     info@dillinlab-berkeley.org