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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Elevated Fecal Mitochondrial DNA from Symptomatic Norovirus Infections Suggests Potential Health Relevance of Human Mitochondrial DNA in Fecal Source Tracking.Zhu, Kevin J; Suttner, Brittany; Knee, Jackie; Capone, Drew; Moe, Christine L; Stauber, Christine E; Konstantinidis, Kostas T; Wallach, Thomas E; Pickering, Amy J; Brown, Joe (2022-05-18)An end goal of fecal source tracking (FST) is to provide information on risk of transmission of waterborne illnesses associated with fecal contamination. Ideally, concentrations of FST markers in ambient waters would reflect exposure risk. Human mtDNA is an FST marker that is exclusively human in origin and may be elevated in feces of individuals experiencing gastrointestinal inflammation. In this study, we examined whether human mtDNA is elevated in fecal samples from individuals with symptomatic norovirus infections using samples from the United States (US), Mozambique, and Bangladesh. We quantified hCYTB484 (human mtDNA) and HF183/BacR287 (human-associated ) FST markers using droplet digital polymerase chain reaction. We observed the greatest difference in concentrations of hCYTB484 when comparing samples from individuals with symptomatic norovirus infections versus individuals without norovirus infections or diarrhea symptoms: log increase of 1.42 in US samples (3,820% increase, -value = 0.062), 0.49 in Mozambique (308% increase, -value = 0.061), and 0.86 in Bangladesh (648% increase, -value = 0.035). We did not observe any trends in concentrations of HF183/BacR287 in the same samples. These results suggest concentrations of fecal mtDNA may increase during symptomatic norovirus infection and that mtDNA in environmental samples may represent an unambiguously human source-tracking marker that correlates with enteric pathogen exposure risk.
Evaluation of Gyp7 Protein Ability to Coordinate and Regulate Mitochondrial Genomes StabilityDiDone, Louis; The College at Brockport (2006-06-01)Cellular creation of adenosine triphosphate, ATP, is essential for eukaryotic cells to function properly. The ATP molecule drives most of the biochemical and metabolic pathways of the cell. The cell's ATP is produced in the mitochondria. Mutations within the genome of the mitochondria will alter the cell's ability to generate A TP. Preliminary work has shown that loss of the Gyp 7p in Saccharomyces cerevisiae blocks the ability of mitochondria to properly function. The Gyp 7 gene was isolated using a technique called two-hybrid analysis with a known mitochondrial protein called llvSp, which was used as 'bait'. We have shown that a deletion of the Gyp7 gene is not essential for cellular viability in S. cerevisiae. We observed that loss of Gyp 7 decreases both the occurrence of point mutations at microsatellite sequences as well as decreasing the rate at which recombination between direct-repeat DNA sequences occurs. This contributes to the effective that cellular respiration mutation rate increase when Gyp7p is removed. Gyp7 encodes for the production of the GTPase-activating protein (GAP) Gyp7p within the Ypt/Rab transport GTPase pathway. This pathway is involved in protein trafficking within the cell.
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.