bims-cytox1 2017-12-17 papers

Biochemistry (Mosc). 2017 Nov;82(11): 1324-1335

Factors beyond Enolase 2 and Mitochondrial Lysyl-tRNA Synthetase Precursor Are Required for tRNA Import into Yeast Mitochondria.

M V Baleva, M Meyer, N Entelis, I Tarassov, P Kamenski, B Masquida.

In yeast, the import of tRNALys with CUU anticodon (tRK1) relies on a complex mechanism where interaction with enolase 2 (Eno2p) dictates a deep conformational change of the tRNA. This event is believed to mask the tRNA from the cytosolic translational machinery to re-direct it towards the mitochondria. Once near the mitochondrial outer membrane, the precursor of the mitochondrial lysyl-tRNA synthetase (preMsk1p) takes over enolase to carry the tRNA within the mitochondrial matrix, where it is supposed to participate in translation following correct refolding. Biochemical data presented in this report focus on the role of enolase. They show that despite the inability of Eno2p alone to form a complex with tRK1, mitochondrial import can be recapitulated in vitro using fractions of yeast extracts sharing either recombinant or endogenous yeast Eno2p as one of the main components. Taken together, our data suggest the existence of a protein complex containing Eno2p that is involved in RNA mitochondrial import.

DOI: https://doi.org/10.1134/S0006297917110104

Mitochondrion. 2017 Dec 07. pii: S1567-7249(17)30219-2. [Epub ahead of print]

Leber's hereditary optic neuropathy caused by a mutation in mitochondrial tRNAThr in eight Chinese pedigrees.

Juanjuan Zhang, Yanchun Ji, Xiaoling Liu, Jie Chen, Bibin Wang, Minglian Zhang, Min-Xin Guan.

PURPOSE: The purpose of this study was to investigate the pathophysiology underlying Leber's hereditary optic neuropathy (LHON)-associated mitochondrial tRNA mutation.
METHODS: Severn hundred ninety-seven Han Chinese subjects underwent clinical and genetic evaluation and analysis of mitochondrial DNA (mtDNA). The cybrid cell lines were constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mtDNA-less (ρo) cells. These cell lines were assayed by tRNA Northern blot and Western blot analyses, respiratory enzymatic activities, the rate of ATP production and the generation of reactive oxygen species.
RESULTS: The tRNAThr 15927G>A mutation was identified in eight probands with suggestively maternal inheritance among 352 Han Chinese probands lacking these known LHON-associated mtDNA mutations. The m.15927G>A mutation affected a highly conserved guanine at position 42 at the anticodon-stem of tRNAThr, destabilizing the conservative base pairing (28C-42G). We therefore hypothesized that the m.15927G>A mutation, and altered the structure and function of tRNAThr. Northern blot analysis revealed 60% decrease in the steady-state level of tRNAThr in the mutant cell lines. Western blot analysis showed the variable reductions of 4 mtDNA encoding proteins, especially for marked decrease of ND1 and CYTB observed in mutant cell lines. Furthermore, we demonstrated that the m.15927G>A mutation decreased the activities of mitochondrial complexes I and III, markedly diminished mitochondrial ATP levels, and increased the production of reactive oxygen species in the mutant cells.
CONCLUSIONS: Our data demonstrated the first mitochondrial tRNA mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON.

Keywords: Chinese; Leber's hereditary optic neuropathy (LHON); Metabolism; Mitochondrial DNA; Mutation; Pathophysiology; tRNA

DOI: https://doi.org/10.1016/j.mito.2017.12.003

Mitochondrion. 2017 Dec 07. pii: S1567-7249(16)30241-0. [Epub ahead of print]

Succinate dehydrogenase: Prospect for neurodegenerative diseases.

Mohammad Jodeiri Farshbaf, Abbas Kiani-Esfahani.

Onset of Alzheimer's, Parkinson's and Huntington's diseases as neurodegenerative disorders is increased by age. Alleviation of clinical symptoms and protection of neurons against degeneration are the main aspects of researches to establish new therapeutic strategies. Many studies have shown that mitochondria play crucial roles in high energy demand tissues like brain. Impairments in mitochondrial activity and physiology can makes neurons vulnerable to stress and degeneration. Succinate dehydrogenase (SDH) connects tricarboxylic cycle to the electron transport chain. Therefore, dysfunction of the SDH could impair mitochondrial activity, ATP generation and energy hemostasis in the cell. Exceed lipid synthesis, induction of the excitotoxicity in neurodegenerative disorders could be controlled by SDH through direct and indirect mechanism. In addition, mutation in SDH correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as a key regulator in neuroprotection. This review will present recent findings which are about SDH activity and related pathways which could play important roles in neuronal survival. Additionally, we will discuss about all possibilities which candidate SDH as a neuroprotective agent.

Keywords: Excitotoxicity; Lipid synthesis; Mitochondria; Neurodegenerative disorders; Neuroprotection; Succinate dehydrogenase

DOI: https://doi.org/10.1016/j.mito.2017.12.002

Am J Kidney Dis. 2017 Dec 07. pii: S0272-6386(17)31014-4. [Epub ahead of print]

Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report.

Sandrine Lemoine, Marine Panaye, Maud Rabeyrin, Elisabeth Errazuriz-Cerda, Bénédicte Mousson de Camaret, Philippe Petiot, Laurent Juillard, Fitsum Guebre-Egziabher.

We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. Mutations in the MT-ATP6 gene of mtDNA have been shown to cause NARP syndrome without renal involvement. We report a patient who had NARP syndrome diagnosed at age 11 years in whom glomerular proteinuria was present very early after diagnosis. Although neurologic manifestations were stable over time, he developed worsening proteinuria and kidney function. He started dialysis therapy at age 21 years. Kidney biopsy confirmed the mitochondrial cytopathy histologically, with abnormal mitochondria seen on electron microscopy. The MT-ATP6 gene mutation was detected in the kidney biopsy specimen.

Keywords: NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome; case report; dialysis; end-stage renal disease (ESRD); focal segmental glomerulosclerosis (FSGS); heteroplasmy; mitochondrial cytopathy; proteinuria; reduced kidney function; renal biopsy

DOI: https://doi.org/10.1053/j.ajkd.2017.09.020