Biology subjects

Dillin, A.

Publications and source records attributed to Dillin, A..

4 recordsLinked to original sources

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↗

bioRxiv2019

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor {beta} (TGF{beta}) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGF{beta} signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGF{beta} receptors, or pharmacological inhibition of TGF{beta} signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGF{beta} signaling.

neuroscience↗

bioRxiv2018

Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

Somatic cells can be reprogrammed into pluripotent stem cells by the forced expression of the OCT4, SOX2, KLF4 and c-MYC transcription factors. This process requires the reshaping of not only epigenetic landscapes, but the global remodeling of cell identity, structure, and function including such basic processes of metabolism and organelle form and function. Cellular reprogramming is a stochastic process with only a marginally measureable fraction of cells successfully crossing these, and many other, cellular epitomes to acquire the fully pluripotent state. We hypothesize that this variation is due, in part, by variable regulation of the proteostasis network and its influence upon the protein folding environment within cells and their organelles upon the remodeling process. We find that the endoplasmic reticulum unfolded protein response (UPRER), the heat-shock response (HSR) and the mitochondrial unfolded protein response (UPRmt), which monitor and ensure the quality of the proteome of, respectively, the ER, the cytosol and the mitochondria during stress, are activated during cellular reprogramming. Particularly, we find that the UPRER is essential for reprograming, and ectopic, transient activation of the UPRER, either genetically or pharmacologically, enhances the success of cells to reach a pluripotent state. Finally, and most revealing, we find that stochastic activation of the UPRER can predict the reprogramming efficiency of naive cells. The results of these experiments indicate that the low efficiency and stochasticity of cellular reprogramming is partly the result of the inability to initiate a proper ER stress response for remodeling of the ER and its proteome during the reprogramming process. The results reported here display only one aspect of the proteostasis network and suggest that proper regulation of many more components of this network might be essential to acquire the pluripotent state.

cell biology↗

bioRxiv2018

A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy.

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPRER) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPRER-induced longevity.

cell biology↗