Track topics on Twitter Track topics that are important to you
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.
This article was published in the following journal.
Name: PLoS genetics
Aging is associated with progressive decline in cardiac structure and function. Accumulating evidence in model organisms and humans links cardiac aging to mitochondrial regulation, encompassing a comp...
Mitochondria are organelles descended from an endosymbiosed bacterium, and many bacterial toxins impair mitochondria, likely as an echo of ancient bacterial warfare. However, the signal transduction p...
The RNA-binding protein GRSF1 (G-rich RNA sequence-binding factor 1) critically maintains mitochondrial homeostasis. Accordingly, loss of GRSF1 impaired mitochondrial respiration and increased the lev...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide a...
Both α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that αSyn and its missense mutant, A53...
An association between insulin resistance and mitochondrial dysfunction has been observed in aging, T2D, and in offspring of patients with T2D. It remains to be determined whether pharmac...
Mitochondrial myopathies include various inherited diseases that are caused by damage to the mitochondria, energy-producing structures that fuel the body's processes. The main symptoms are...
Our central hypothesis is that oral CoQ10 is a safe and effective treatment for children with inborn errors of mitochondrial energy metabolism due to defects in specific respiratory chain ...
It has been suggested that mitochondrial dysfunction might play a role in the development of diabetic cardiomyopathy. From animal studies, it has been suggested that an altered PPAR and PG...
The primary aim of the study is to demonstrate that mitochondrial dysfunction occurs in both skeletal muscle and circulating platelets of severely septic and septic shock ICU-admitted pati...
A cellular response to environmental insults that cause disruptions in PROTEIN FOLDING and/or accumulation of defectively folded protein in the ENDOPLASMIC RETICULUM. It consists of a group of regulatory cascades that are triggered as a response to altered levels of calcium and/or the redox state of the endoplasmic reticulum. Persistent activation of the unfolded protein response leads to the induction of APOPTOSIS.
In vitro fertilization technique that uses mitochondrial DNA from a healthy donor in order to prevent the transmission of MITOCHONDRIAL DISEASE.
The alpha subunit of mitochondrial trifunctional protein. It contains both enoyl-CoA hydratase activity (EC 126.96.36.199) and long-chain-3-hydroxyacyl-CoA dehydrogenase activity (EC 188.8.131.52). There are four of these alpha subunits in each mitochondrial trifunctional protein molecule.
A mitochondrial uncoupling protein that is expressed in many tissues and exhibits the greatest expression in SKELETAL MUSCLE. It regulates mitochondrial ATP production and the generation of REACTIVE OXYGEN SPECIES.
Mitochondrial anion carrier proteins that function as dimers and form proton channels in the INNER MITOCHONDRIAL MEMBRANE which creates proton leaks and uncouples OXIDATIVE PHOSPHORYLATION from ATP synthesis, resulting in the generation of heat instead of ATP.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...