bims-cytox1 2018-09-23 papers

Issue of 2018–09–23
two papers selected by
Gavin McStay, Staffordshire University

Prog Neurobiol. 2018 Sep 13. pii: S0301-0082(18)30065-0. [Epub ahead of print]

New insights into the complex role of mitochondria in Parkinson's disease.

Anne Grünewald, Kishore R Kumar, Carolyn M Sue.

New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson's disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the development of PD treatments that target mitochondria, we aim to give an overview of the literature published in the last three decades on the significance of mitochondria in the pathogenesis of PD. We describe the contribution of mitochondrial genome alterations and PD-associated genes to mitochondrial maintenance. We highlight mitophagy as a key mechanism in neurodegeneration. Moreover, we focus on the reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. We discuss a novel trafficking pathway involving mitochondrial-derived vesicles within the context of PD and provide a synopsis of the most recently emerging topics in PD research with respect to mitochondria. This includes the relationship between mitochondria and cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrial stress response and the role of micro RNAs in the aetiology of PD. In addition, recent studies have challenged the neuro-centric view of PD pathology, moving microglia and astrocytes into the research spotlight. Greater insights into these mechanisms may hold the key for the development of novel targeted therapies, addressing the need for a disease-modifying treatment, which has remained elusive to date.

Keywords: Parkinson's disease; endogenous PD models; fibroblasts; glia cells; iPSC-derived neurons; micro RNA; mitochondria; mitochondrial-derived vesicles; mitophagy; neurodegeneration; respiratory chain complexes

DOI: https://doi.org/10.1016/j.pneurobio.2018.09.003

Mitochondrion. 2018 Sep 12. pii: S1567-7249(18)30113-2. [Epub ahead of print]

Frequency and association of mitochondrial genetic variants with neurological disorders.

Ana Carolina P Cruz, Adriano Ferrasa, Alysson R Muotri, Roberto H Herai.

Mitochondria are small cytosolic organelles and the main source of energy production for the cells, especially in the brain. This organelle has its own genome, the mitochondrial DNA (mtDNA), and genetic variants in this molecule can alter the normal energy metabolism in the brain, contributing to the development of a wide assortment of Neurological Disorders (ND), including neurodevelopmental syndromes, neurodegenerative diseases and neuropsychiatric disorders. These ND are comprised by a heterogeneous group of syndromes and diseases that encompass different cognitive phenotypes and behavioral disorders, such as autism, Asperger's syndrome, pervasive developmental disorder, attention deficit hyperactivity disorder, Huntington disease, Leigh Syndrome and bipolar disorder. In this work we carried out a Systematic Literature Review (SLR) to identify and describe the mitochondrial genetic variants associated with the occurrence of ND. Majority of genetic variants found in mtDNA were associated with Single Nucleotide Polimorphisms (SNPs), ~79%, with ~15% corresponding to deletions, ~3% to Copy Number Variations (CNVs), ~2% to insertions and another 1% included mtDNA replication problems and genetic rearrangements. We also found that most of the variants were associated with coding regions of mitochondrial proteins but were also found in regulatory transcripts (tRNA and rRNA) and in the D-Loop replication region of the mtDNA. After analysis of mtDNA deletions and CNV, none of them occur in the D-Loop region. This SLR shows that all transcribed mtDNA molecules have mutations correlated with ND. Finally, we describe that all mtDNA variants found were associated with deterioration of cognitive (dementia) and intellectual functions, learning disabilities, developmental delays, and personality and behavior problems.

Keywords: Genetic variants; Mitochondrial DNA; Neurodegenerative diseases; Neurodevelopmental syndromes; Neurological disorders; Neuropsychiatric disorders; Systematic literature review

DOI: https://doi.org/10.1016/j.mito.2018.09.005