Browsing by Subject "OPA1"

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  • Forsström, Saara; Jackson, Christopher B.; Carroll, Christopher J.; Kuronen, Mervi; Pirinen, Eija; Pradhan, Swagat; Marmyleva, Anastasiia; Auranen, Mari; Kleine, Iida-Marja; Khan, Nahid A.; Roivainen, Anne; Marjamäki, Paivi; Liljenbäck, Heidi; Wang, Liya; Battersby, Brendan J.; Richter, Uwe; Velagapudi, Vidya; Nikkanen, Joni; Euro, Liliya; Suomalainen, Anu (2019)
    Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.
  • Battersby, Brendan; Richter, Uwe; Safronov, Omid (2019)
    Proteotoxicity has long been considered a key factor in mitochondrial dysfunction and human disease. The origin of the endogenous offending toxic substrates and the regulatory pathways to deal with these insults, however, have remained unclear. Mitochondria maintain a compartmentalized gene expression system that in animals is only responsible for synthesis of 1% of the organelle proteome. Because of the relatively small contribution of the mitochondrial genome to the overall proteome, the synthesis and quality control of these nascent chains to maintain organelle proteostasis has long been overlooked. However, recent research has uncovered mechanisms by which defects to the quality control of mitochondrial gene expression are linked to a novel cellular stress response that impinges upon organelle form and function and cell fitness. In this review, we discuss the mechanisms for a key event in the response: activation of the metalloprotease OMA1. This severs the membrane tether of the dynamin-related GTPase OPA1, which is a critical determinant for mitochondrial morphology and function. We also highlight the evolutionary conservation from bacteria of these quality-control mechanisms to maintain membrane integrity, gene expression, and cell fitness.
  • Richter, Uwe; Ng, Kah Ying; Suomi, Fumi; Marttinen, Paula; Turunen, Taina; Jackson, Christopher; Suomalainen, Anu; Vihinen, Helena; Jokitalo, Eija; Nyman, Tuula A.; Isokallio, Marita A.; Stewart, James B.; Mancini, Cecilia; Brusco, Alfredo; Seneca, Sara; Lombes, Anne; Taylor, Robert W.; Battersby, Brendan J. (2019)
    Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.
  • Majander, Anna; Joao, Catarina; Rider, Andrew T.; Henning, G. Bruce; Votruba, Marcela; Moore, Anthony T.; Yu-Wai-Man, Patrick; Stockman, Andrew (2017)
    PURPOSE. Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. METHODS. We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. RESULTS. Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log(10) unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. CONCLUSIONS. Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.