Browsing Graduate Student Dissertations & Theses by Subject "INDUCED"
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MECHANISM OF ANT1-INDUCED HUMAN DISEASES AND STRESS SIGNALINGAdenine nucleotidetranslocase(Ant) is a mitochondrial inner membraneprotein, the primaryfunction of which is to mediate the ADP/ATP exchange acrossthe inner membrane. Missense mutations in Ant1, the skeletal muscle-and heart-specificisoform, induce human disordersincluding autosomal dominant ProgressiveExternalOpthalmoplegia(adPEO), cardiomyopathyand myopathy. Several models were proposed to interpret the pathogenesis of mutant Ant1-induced diseases, but no consensus has been reached.Our lab has previouslyfound that mutant Aac2, the homologof Ant1 in yeast, causes cell death due to the mitochondrialbiogenesis defect. In the present study, we provided biochemical evidencesupporting the idea that themutant Aac2 proteins are misfolded, which derailsthe proteostasis on the inner membrane.We found that the assemblyand stability of multipleprotein complexeson the inner membrane are affected, including those involved in mitochondrialrespirationand protein transport. In human cells, the mutant Ant1 proteinshave reduced steady-state levels and increased degradation, consistent with misfolding and increased susceptibility to protein quality control machineries. In the second part of thework, we sought to identify the cellularsignalingpathways that respond to Ant1-induced proteostatic stress on the mitochondrialinner membrane. We generatedANT1alleles that have enhanced toxicity and are able to induce proteostatic stress on the inner membrane in human. Although these mutant Ant1 proteins only mildly affectmitochondrialrespiration, they trigger robust transcriptional responses in the nucleus to remodel cellular signaling. The upregulationof the cytosolic chaperone/ubiquitin-proteasome systems, and the downregulation of mTOR signaling may serveas adaptiveresponses to mitigate mitochondrial PrecursorOver-AccumulationStress (mPOS), a novel pathway of cell death recently discovered in yeast. We also found that humancells respond to mitochondrialinner membrane stress by increasingEgr1 signaling and the alternative splicing of many genes important for cell survival/deathcontrol. Insummary, the data suggested that protein misfoldingcauses Ant1-induced pathogenesisin human diseases. Our study provided support for mitochondria-induced proteostatic stress in the cytosol (or mPOS) in human cells. We also identified several novel mitochondria-to-nucleus signaling pathways, which may help in developingtherapeutic interventionsfor the treatmentof mitochondria-induced pathologies.