Mitochondrial protein import clogging as a novel mechanism of cell stress and degenerative disease
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mitochondrial Precursor Overaccumulation Stress
autosomal dominant Progressive External Ophthalmoplegia
adenine nucleotide translocase 1
mitochondrial protein import stress
mitochondrial protein import clogging
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MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUSPerl, Andras; Doherty, Edward (2014)Systemic lupus erythematosus (SLE) is an autoimmune disorder, characterized by T cell and B cell dysfunction. SLE mitochondria have been shown to be dysfunctional with increased mass, mitochondrial potential, decreased ATP, elevated reactive oxygen species (ROS) and reactive nitrogen species (RNS) concentrations, and altered Ca2+ stores. Drug treatments that target the mitochondria have shown efficacy in treating SLE. Here we have investigated electron transport chain (ETC) activity in SLE, to better understand the causes of mitochondrial dysfunction in SLE. We have found that mitochondrial complexes I and IV of the ETC have elevated respiration in SLE compared to healthy controls after both overnight resting and anti-CD3/CD28 stimulation. We have also shown that SLE complex I is resistant to NO inhibition of respiration. SLE peripheral blood lymphocytes (PBL) have increased S-nitrosylation (SNO) while immunoprecipitated complex I had decreased SNO of proteins compared to healthy controls. The drug Nacetylcysteine (NAC) was able to inhibit complex I activity in SLE, and was found to reduce the amount of complex I protein NDUFS3 after 15 minutes as measured by western blotting. These results have led us to the conclusion that SLE mitochondrial complex I is in an active form which is resistant to SNO and is driving the production of ROS and RNS that are associated with SLE. The drug NAC is able to inhibit complex I respiration which may have therapeutic efficacy by reducing the ROS and RNS stress in SLE.
MITOCHONDRIAL PROTEINS AS TUMOR MARKERS AND ANTI-CANCER DRUG TARGETSSheikh, Saeed; Babbar, Mansi (2017)Cancer is a major cause of morbidity and mortality. Identification and characterization of novel biomarkers are expected to facilitate early diagnosis and improve prognosis of human malignancies. Increasing number of studies have linked tumor progression with metabolic reprogramming. However, the players involved are not fully discovered. Therefore, understanding the cancer cell plasticity may offer a successful approach for an anti-cancer strategy. In this regard, we report the functional characterization of Coiled-coil Helix Tumor and Metabolism 1 (CHTM1) and KM1 as important regulator of cancer cell metabolism.CHTM1 is localized in cytosol and mitochondrial inter-membrane spaceand regulates mitochondrial activity. Our results demonstrate that MIA40 appears to alterCHTM1 mitochondrial localizationand stability. Further, CHTM1 cysteineresiduesinvolved in CHTM1 folding modulatescellular distributionof CHTM1. Importantly, alterations in CHTM1 expression in cancer cells affect mitochondrial activity. Given thatmitochondria play an important role in cellular response to nutrient stress, we sought to analyze the role of CHTM1 in glucose/glutamine-deprived conditions. Wehave found thatCHTM1 deficiency enhancescancer cell sensitivityto glucose/glutamine starvation and metformin treatment. Additionally, increased sensitivity of CHTM1-deficient cells to metabolic stress could be in part due to inability to activate fatty acid oxidation. Further, targeting CHTM1 expression in cancer cells reduce fatty acid oxidation causing decrease in substrate availability under metabolic stress conditions. This can explain the increase in autophagy and protein catabolism in CHTM1-deficient cancer cells under metabolic stress conditions. Mechanistic studies suggest that CHTM1-mediated alterations in cancer cell metabolism under stress conditions involve modulation of PGC1 alpha-CREB-PKC signaling.We further demonstrate that under metabolic stress, CHTM1 deficiency activates p38-AIF1pathway leading to increased cell death. CHTM1 negatively regulates p38 and interacts with AIF1 alteringAIF1release frommitochondria under metabolic stress conditions.These findings are highly significant because alterations in cancer cell metabolism are linked to pathogenesis of cancer. Most importantly, multiple human malignancies associated with breast, colon and lung tissuesshow increase in CHTM1 expression. CHTM1 appears to be a high value tumor marker, that has the potential tofacilitate earlydiagnosis of human malignancies and could also serve as a target to develop novel therapeutics to manage human malignancies. In the second part of this manuscript, we report the characterization of a novel protein temporarily named as KM1. Our results indicate that KM1 is localized inthemitochondrial inner membrane and regulates mitochondrial activity. Metabolic stress-induced increased cell death is noted in KM1 knockout cancer cells, a finding consistent with the defective mitochondria in KM1-deficient cells. Our results further demonstrate that under metabolic stress KM1 regulates mitochondrial-mediated cell death. Most importantly, KM1 levels are upregulated in breast and lung cancer tissues.Collectively, our results suggest that CHTM1 and KM1 are novel proteins and are involved in regulating cancer cell metabolism.
The Effects of KU70 on Mitochondrial Stability in the Saccharomyces cerevisiaeSia, Rey; Ortega, Bernardo; Tsubota, Stuart; Burkhart, Allyson (2016-06-23)The purpose of this experiment is to determine the role of KU70, a nuclear gene, in maintaining mitochondrial DNA in the model organism Saccharomyces cerevisiae, the budding yeast. The mitochondrion is an organelle in eukaryotes that produces much of the ATP used by a cell. ATP, or adenosine-triphosphate, is a molecule within a cell that provides energy for cellular functions via its high energy holding phosphate bonds. Mitochondria have their own genomes, separate from nuclear DNA, which encodes many proteins needed for cellular respiration. Mutations can occur in the mitochondria of humans that could result in decrease or loss of mitochondrial function, which leads to neuromuscular or neurodegenerative diseases. The KU70 gene is actually a subunit of a heterodimer that works in coordination with KU80. These genes function in the stability of the genome during DNA double-strand break (DSB) repair through nonhomologous end-joining (NHEJ) and telomere maintenance. The goal of this project is to determine the effects caused by the loss of KU70 on the mitochondrial stability. By completing two different assays, respiration loss and direct repeat-mediated deletion (DRMD), the role of the gene can be predicted. The respiration loss assay showed a 1.4-fold decrease (p=0.027) in spontaneous respiration loss compared to the wild type strain. The rate of DRMD events in the nuclear and mitochondrial genomes showed 1.42-fold decrease (p= 0.014) in spontaneous mutation rates in nuclear DNA and a 1.69-fold decrease (p=0.075) in mitochondrial DNA compared to the wild type. Finally, the induced-DRMD assay showed a 1.23-fold decrease (p=0.029) in homologous recombination events compared to the wild type. These results suggest that Ku-independent end joining may be a more efficient repair pathway and promote mitochondrial stability.