Browsing by Subject "MITOPHAGY"

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  • Katajisto, Pekka; Doehla, Julia; Chaffer, Christine L.; Pentinmikko, Nalle; Marjanovic, Nemanja; Iqbal, Md Sharif; Zoncu, Roberto; Chen, Walter; Weinberg, Robert A.; Sabatini, David M. (2015)
    By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.
  • Majander, Anna; Bowman, Richard; Poulton, Joanna; Antcliff, Richard J.; Reddy, M. Ashwin; Michaelides, Michel; Webster, Andrew R.; Chinnery, Patrick F.; Votruba, Marcela; Moore, Anthony T.; Yu-Wai-Man, Patrick (2017)
    Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m. 3460G>A, m. 11778G>A or m. 14484T>C. Results In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m. 3460G>A and m. 14484T>C mutations compared with the m. 11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) >= 0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA Conclusions Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.
  • Long, Maeve; McWilliams, Thomas G. (2020)
    Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.
  • McWilliams, Thomas; Barini, Erica; Pohjolan-Pirhonen, Risto; Brooks, Simon P.; Singh, François; Burel, Sophie; Balk, Kristin; Kumar, Atul; Montava-Garriga, Lambert; Prescott, Alan R.; Hassoun, Sidi Mohamed; Mouton-Liger, François; Ball, Graeme; Hills, Rachel; Knebel, Axel; Ulusoy, Ayse; Di Monte, Donato A.; Tamjar, Jevgenia; Antico, Odetta; Fears, Kyle; Smith, Laura; Brambilla, Riccardo; Palin, Eino; Valori, Miko; Eerola-Rautio, Johanna; Tienari, Pentti; Corti, Olga; Dunnett, Stephen B.; Ganley, Ian G.; Suomalainen, Anu; Muqit, Miratul M.K. (2018)
    Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.
  • Vannini, Nicola; Campos, Vasco; Girotra, Mukul; Trachsel, Vincent; Rojas-Sutterlin, Shanti; Tratwal, Josefine; Ragusa, Simone; Stefanidis, Evangelos; Ryu, Dongryeol; Rainer, Pernille Y.; Nikitin, Gena; Giger, Sonja; Li, Terytty Y.; Semilietof, Aikaterini; Oggier, Aurelien; Yersin, Yannick; Tauzin, Loic; Pirinen, Eija; Cheng, Wan-Chen; Ratajczak, Joanna; Canto, Carles; Ehrbar, Martin; Sizzano, Federico; Petrova, Tatiana V.; Vanhecke, Dominique; Zhang, Lianjun; Romero, Pedro; Nahimana, Aimable; Cherix, Stephane; Duchosal, Michel A.; Ho, Ping-Chih; Deplancke, Bart; Coukos, George; Auwerx, Johan; Lutolf, Matthias P.; Naveiras, Olaia (2019)
    It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD(+)-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD(+)-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.