• From posttranslational modifications to disease phenotype: A substrate selection hypothesis in neurodegenerative diseases

      Baskakov, Ilia V. (MDPI AG, 2021-01-18)
      A number of neurodegenerative diseases including prion diseases, tauopathies and synu-cleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region-and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin. © 2021 by the author.
    • Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination

      Oshima, Yumiko; Cartier, Etienne; Boyman, Liron; Verhoeven, Nicolas; Polster, Brian M; Huang, Weiliang; Kane, Maureen; Lederer, W Jonathan; Karbowski, Mariusz (Rockefeller University Press, 2021-04-14)
      Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell ("mosaic distribution"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins. © 2021 Oshima et al.