UC Berkeley

Mitochondria are an essential organelle, serving as a key site of energy production in metazoans. Animals have complex systems for monitoring the health and proteostasis of mitochondria, and activate multiple quality control mechanisms in response to dysfunction. Using the nematode Caenorhabditis elegans, we investigated mitochondrial health, dysfunction, and stress signaling in two different systems.

Dysfunction of mitochondrial DNA replication machinery is a common cause of mitochondrial diseases. The minimal mammalian replisome is made up of DNA polymerase gamma, replicative helicase Twinkle, and single-stranded DNA binding protein. Recently, a sequence homolog of Twinkle was uncovered in the nematode C. elegans. Here, we characterized this homolog, twnk-1, and report that while twnk-1 does not appear function as the primary mitochondrial DNA replicative helicase in this species, as loss of twnk-1 does not result in reduce mitochondrial DNA levels, or result in other expected mitochondrial dysfunctions such as reduced oxygen consumption rates, increased sensitivity to metabolic perturbations, or reduced muscle function. However, twnk-1 mutants exhibit phenotypes associated with mitochondrial stress, including reduced fecundity, an activation of the mitochondrial unfolded protein response (UPRmt), and mitochondrial fragmentation. Our results suggest that in C. elegans, twnk-1 does not function as the mitochondrial DNA replicative helicase, but has an alternative function in regulating mitochondrial function.

In a second project, we focused on the UPRmt, a transcriptional program initiated when mitochondrial proteostasis is challenged. Previous work from our lab shows that when mitochondrial health is challenged in neurons alone, they signal to distal tissues, activating the UPRmt in the intestine. This causes hormesis as shown through extended lifespan. We found that when the UPRmt component and chromatin modifier PHF8/jmjd-1.2a is overexpressed in a second neural cell type, astrocyte-like cephalic sheath glia, they signal the UPRmt to distal tissues as well. We used two UPRmt reporters to investigate this effect, and to dissect the details of the two branches of UPRmt signaling. Glial UPRmt induced hormesis as shown through extended lifespan, as well as resistance to the mitochondrial stressor paraquat. This work contributes to the growing field of glia biology and supports the hypothesis that glia are actively involved in information processing and signaling.