bims-cytox1 2020-06-07 papers

Issue of 2020–06–07
six papers selected by
Gavin McStay, Staffordshire University

Int J Mol Sci. 2020 May 28. pii: E3820. [Epub ahead of print]21(11):

Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways.

Jia Xin Tang, Kyle Thompson, Robert W Taylor, Monika Oláhová.

The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which-given their dual-genetic control-requires tight co-regulation of two evolutionarily distinct gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors-also known as the LYRM (leucine-tyrosine-arginine motif) proteins-together with the mitochondrial acyl carrier protein (ACP)-regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.

Keywords: LYRM proteins; OXPHOS assembly factors; OXPHOS biogenesis; mitochondrial ACP; mitochondrial gene expression; mitochondrial import

DOI: https://doi.org/10.3390/ijms21113820

Cureus. 2020 Apr 27. 12(4): e7862

Late-onset Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) Syndrome in a 63-year-old Patient.

Hassan Abdullah, Syed Shah, Humza Husain, Furqan Hassan, Hamza Maqsood.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) usually manifests in early life. Clinical hallmarks of the disease are mitochondrial myopathies, encephalopathy with stroke-like episodes, seizures, and lactic acidosis. It rarely manifests in late adulthood. Here we present the case of a 63-year-old female patient who developed recurrent stroke-like symptoms with typical resolving and remitting pattern of findings on imaging. Later on, it was confirmed as a case of MELAS upon genetic analysis.

Keywords: encephalopathy; lactic acidosis; melas; mitochondrial dna mutation; mri; myopathy; seizures; stroke

DOI: https://doi.org/10.7759/cureus.7862

Genet Mol Biol. 2020 ;pii: S1415-47572020000400109. [Epub ahead of print]43(2): e20180271

Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review.

Eduardo Perrone, Thiago R Cavole, Manuella G Oliveira, Luiza do A Virmond, Marina de França B Silva, Maria de Fatima F Soares, Simone Brasil de O Iglesias, Ariane Falconi, Juliana S Silva, Viviane Nakano, Maria Fernanda Milanezi, Carmen Silvia C Mendes, Marco Antonio Curiati, Cecília Micheletti.

Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.

DOI: https://doi.org/10.1590/1678-4685-GMB-2018-0271

Mol Ther Methods Clin Dev. 2020 Jun 12. 17 1071-1078

A Single Intravenous Injection of AAV-PHP.B-hNDUFS4 Ameliorates the Phenotype of Ndufs4 -/- Mice.

Pedro Silva-Pinheiro, Raffaele Cerutti, Marta Luna-Sanchez, Massimo Zeviani, Carlo Viscomi.

Leigh syndrome, or infantile necrotizing subacute encephalopathy (OMIM #256000), is one of the most common manifestations of mitochondrial dysfunction, due to mutations in more than 75 genes, with mutations in respiratory complex I subunits being the most common cause. In the present study, we used the recently described PHP.B serotype, characterized by efficient capacity to cross the blood-brain barrier, to express the hNDUFS4 gene in the Ndufs4 -/- mouse model of Leigh disease. A single intravenous injection of PHP.B-hNDUFS4 in adult Ndufs4 -/- mice led to a normalization of the body weight, marked amelioration of the rotarod performance, delayed onset of neurodegeneration, and prolongation of the lifespan up to 1 year of age. hNDUFS4 protein was expressed in virtually all brain regions, leading to a partial recovery of complex I activity. Our findings strongly support the feasibility and effectiveness of adeno-associated viral vector (AAV)-mediated gene therapy for mitochondrial disease, particularly with new serotypes showing increased permeability to the blood-brain barrier in order to achieve widespread expression in the central nervous system.

Keywords: AAV; Leigh syndrome; Ndufs4; OXPHOS; PHP.B; complex I; gene therapy; mitochondrial diseases

DOI: https://doi.org/10.1016/j.omtm.2020.04.026

FEBS J. 2020 Jun 03.

Functional coupling of presequence processing and degradation in human mitochondria.

Cansu Kücükköse, Asli Aras Taskin, Adinarayana Marada, Tilman Brummer, Sven Dennerlein, Friederike-Nora Vögtle.

The mitochondrial proteome is built and maintained mainly by import of nuclear-encoded precursor proteins. Most of these precursors use N-terminal presequences as targeting signals that are removed by mitochondrial matrix proteases. The essential mitochondrial processing protease MPP cleaves presequences after import into the organelle thereby enabling protein folding and functionality. The cleaved presequences are subsequently degraded by peptidases. While most of these processes have been discovered in yeast, characterization of the human enzymes is still scarce. As the matrix presequence peptidase PreP has been reported to play a role in Alzheimer's disease, analysis of impaired peptide turnover in human cells is of huge interest. Here, we report the characterization of HEK293T PreP knockout cells. Loss of PreP causes severe defects in oxidative phosphorylation and changes in nuclear expression of stress response marker genes. The mitochondrial defects upon lack of PreP result from the accumulation of presequence peptides that trigger feedback inhibition of MPP and accumulation of nonprocessed precursor proteins. Also, the mitochondrial intermediate peptidase MIP that cleaves eight residues from a subset of precursors after MPP processing is compromised upon loss of PreP suggesting that PreP also degrades MIP generated octapeptides. Investigation of the PrePR183Q patient mutation associated with neurological disorders revealed that the mutation destabilizes the protein making it susceptible to enhanced degradation and aggregation upon heat shock. Taken together, our data reveal a functional coupling between precursor processing by MPP and MIP and presequence degradation by PreP in human mitochondria that is crucial to maintain a functional organellar proteome.

Keywords: Alzheimer's disease; integrated stress response; mitochondrial proteostasis; precursor protein import; presequence degradation

DOI: https://doi.org/10.1111/febs.15358

Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30010-1. [Epub ahead of print]354 1-61

The biology of Lonp1: More than a mitochondrial protease.

Lara Gibellini, Anna De Gaetano, Mauro Mandrioli, Elia Van Tongeren, Carlo Augusto Bortolotti, Andrea Cossarizza, Marcello Pinti.

Initially discovered as a protease responsible for degradation of misfolded or damaged proteins, the mitochondrial Lon protease (Lonp1) turned out to be a multifaceted enzyme, that displays at least three different functions (proteolysis, chaperone activity, binding of mtDNA) and that finely regulates several cellular processes, within and without mitochondria. Indeed, LONP1 in humans is ubiquitously expressed, and is involved in regulation of response to oxidative stress and, heat shock, in the maintenance of mtDNA, in the regulation of mitophagy. Furthermore, its proteolytic activity can regulate several biochemical pathways occurring totally or partially within mitochondria, such as TCA cycle, oxidative phosphorylation, steroid and heme biosynthesis and glutamine production. Because of these multiple activities, Lon protease is highly conserved throughout evolution, and mutations occurring in its gene determines severe diseases in humans, including a rare syndrome characterized by Cerebral, Ocular, Dental, Auricular and Skeletal anomalies (CODAS). Finally, alterations of LONP1 regulation in humans can favor tumor progression and aggressiveness, further highlighting the crucial role of this enzyme in mitochondrial and cellular homeostasis.

Keywords: CODAS; Colon cancer; LONP1; Lon protease; Mitochondria; Proteotoxic stress; mtDNA

DOI: https://doi.org/10.1016/bs.ircmb.2020.02.005