bims-cytox1 2020-11-01 papers

Issue of 2020–11–01
four papers selected by
Gavin McStay, Staffordshire University

J Inherit Metab Dis. 2020 Oct 25.

Current Progress with Mammalian Models of Mitochondrial DNA Disease.

Mitochondrial disorders make up a large class of heritable diseases that cause a broad array of different human pathologies. They can affect many different organ systems, or display very specific tissue presentation, and can lead to illness either in childhood or later in life. While the over 1200 genes encoded in the nuclear DNA play an important role in human mitochondrial disease, it has been known for over 30 years that mutations of the mitochondria's own small, multicopy DNA chromosome (mtDNA) can lead to heritable human diseases. Unfortunately, animal mtDNA has resisted transgenic and directed genome editing technologies until quite recently. As such, animal models to aid in our understanding of these diseases, and to explore pre-clinical therapeutic research have been quite rare. This review will discuss the unusual properties of animal mitochondria that have hindered the generation of animal models. It will also discuss the existing mammalian models of human mtDNA disease, describe the methods employed in their generation, and will discuss recent advances in the targeting of DNA-manipulating enzymes to the mitochondria and how these may be employed to generate new models. This article is protected by copyright. All rights reserved.

Keywords: Animal models; heteroplasmy; homoplasmy; mitochondrial DNA; mitochondrial disease

DOI: https://doi.org/10.1002/jimd.12324

BMC Biol. 2020 Oct 29. 18(1): 156

The selectivity filter of the mitochondrial protein import machinery.

Sebastian Kreimendahl, Jan Schwichtenberg, Kathrin Günnewig, Lukas Brandherm, Joachim Rassow.

BACKGROUND: The uptake of newly synthesized nuclear-encoded mitochondrial proteins from the cytosol is mediated by a complex of mitochondrial outer membrane proteins comprising a central pore-forming component and associated receptor proteins. Distinct fractions of proteins initially bind to the receptor proteins and are subsequently transferred to the pore-forming component for import. The aim of this study was the identification of the decisive elements of this machinery that determine the specific selection of the proteins that should be imported.
RESULTS: We identified the essential internal targeting signal of the members of the mitochondrial metabolite carrier proteins, the largest protein family of the mitochondria, and we investigated the specific recognition of this signal by the protein import machinery at the mitochondrial outer surface. We found that the outer membrane import receptors facilitated the uptake of these proteins, and we identified the corresponding binding site, marked by cysteine C141 in the receptor protein Tom70. However, in tests both in vivo and in vitro, the import receptors were neither necessary nor sufficient for specific recognition of the targeting signals. Although these signals are unrelated to the amino-terminal presequences that mediate the targeting of other mitochondrial preproteins, they were found to resemble presequences in their strict dependence on a content of positively charged residues as a prerequisite of interactions with the import pore.
CONCLUSIONS: The general import pore of the mitochondrial outer membrane appears to represent not only the central channel of protein translocation but also to form the decisive general selectivity filter in the uptake of the newly synthesized mitochondrial proteins.

Keywords: Chaperones; Ion channel; Mitochondria; Protein targeting; Selectivity filter; TOM complex; Tom40; Tom70

DOI: https://doi.org/10.1186/s12915-020-00888-z

EMBO Mol Med. 2020 Oct 30. e13187

Complex I deficiency and Leigh syndrome through the eyes of a clinician.

Karit Reinson, Katrin Õunap.

Mitochondrial complex I deficiency is associated with a wide range of clinical presentations, including Leigh syndrome. Its genetic causes are heterogeneous, with poor genotype-phenotype correlation. It is impossible to identify the genetic defect of complex I deficiency using clinical observation and metabolic/imaging studies alone. As a result, whole-exome sequencing (WES) is increasingly used in clinical work to identify an underlying genetic defect causing the disease. The article in this issue of EMBO Molecular Medicine by Alahmad et al (2020) is timely and valuable, as it expands on the genotype of mitochondrial complex I deficiency by identifying and characterising pathogenic variants of the NDUFC2 gene in children with Leigh syndrome.

DOI: https://doi.org/10.15252/emmm.202013187

Int J Mol Sci. 2020 Oct 28. pii: E8031. [Epub ahead of print]21(21):

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer.

Seyedeh Tayebeh Ahmadpour, Karine Mahéo, Stéphane Servais, Lucie Brisson, Jean-François Dumas.

Cardiolipins (CLs) are specific phospholipids of the mitochondria composing about 20% of the inner mitochondria membrane (IMM) phospholipid mass. Dysregulation of CL metabolism has been observed in several types of cancer. In most cases, the evidence for a role for CL in cancer is merely correlative, suggestive, ambiguous, and cancer-type dependent. In addition, CLs could play a pivotal role in several mitochondrial functions/parameters such as bioenergetics, dynamics, mitophagy, and apoptosis, which are involved in key steps of cancer aggressiveness (i.e., migration/invasion and resistance to treatment). Therefore, this review focuses on studies suggesting that changes in CL content and/or composition, as well as CL metabolism enzyme levels, may be linked with the progression and the aggressiveness of some types of cancer. Finally, we also introduce the main mitochondrial function in which CL could play a pivotal role with a special focus on its implication in cancer development and therapy.

Keywords: cancer; cardiolipin; mitochondria

DOI: https://doi.org/10.3390/ijms21218031