Henderson, H. R. | Search bioRxiv

bioRxiv2023

Glial-derived mitochondrial signals impact neuronal proteostasis and aging.

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored non-neuronal cells of the nervous system. Here, we found that UPRMT activation in four, astrocyte-like glial cells in the nematode, C. elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Surprisingly, we find that glial cells utilize small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then impact neuron-mediated effects in organismal homeostasis and longevity. One-Sentence SummaryGlial cells sense mitochondrial stress and signal a beneficial stress signal to promote neuronal health and longevity.

genetics↗

bioRxiv2019

Twinkle is not the mitochondrial DNA replicative helicase in C. elegans, but may have alternate mitochondrial functions

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. The replisome is localized to the inner mitochondrial membrane and serves as the site of mitochondrial DNA replication and mitochondrial fission. Recently, a sequence homolog of Twinkle was uncovered in the nematode Caenorhabditis elegans. Here, we characterized this homolog, twnk-1, and report that twnk-1 does not 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. Instead, twnk-1 mutants have increased mitochondrial DNA as they age, and exhibit phenotypes associated with mitochondrial stress, including reduced fecundity, an activation of the mitochondrial unfolded protein response, and mitochondrial fragmentation. Our results suggest in Caenorhabditis elegans, twnk-1 does not function as the mitochondrial DNA replicative helicase, but has an alternative function in regulating mitochondrial function.

molecular biology↗