bims-cytox1 2019-08-04 papers

Issue of 2019–08–04
four papers selected by
Gavin McStay, Staffordshire University

J Neurol Sci. 2019 Jul 10. pii: S0022-510X(19)30300-4. [Epub ahead of print]404 91-100

Genetic heterogeneity of mitochondrial genome in thiamine deficient Leigh syndrome patients.

Shalini Mani, S Narasimha Rao, M V Kranthi Kumar.

In our previously published study, we cared for 165 thiamine deficient Leigh syndrome (LS) patients who presented in acute life threatening conditions with severe neurological abnormalities. However the molecular basis for this atypical phenotype was not explored. This study is an effort to undermine the possible molecular defects in mitochondria of those patients and put-forth an explanation towards this clinical presentation. Protein coding genes of mitochondrial (mt) DNA were sequenced in total 165 LS patients and 94 age matched controls. To understand their pathogenic significance, nucleotide variations were also studied using various in-silico tools. Histochemical and electron microscopic analysis was also done in tissue samples obtained from 23 patients. We observed a very high level of genetic heterogeneity across the mt DNA of all these patients. In the concordance of published literature we also observed a large number of variations in ND5 gene (hot spot for LS). We also observed a total 13 nucleotide variations across COX genes, which is otherwise not common in LS. As per in-silico analysis, many of these variations were suggested to be pathogenic. Histochemical and electron microscopic studies also suggested the defects in the mitochondria of these patients. As these patients were thiamine deficient, hence we propose that genetic defects and thiamine deficiency may together severely affect the ATP levelof these patients, leading to acute and life threatening clinical presentation. Present study has opened up many avenues for further research towards understanding the genetic basis and possible role of thiamine deficiency in LS patients.

Keywords: Complex I; Complex IV; Leigh syndrome; Mitochondrial genome; Thiamine deficiency

DOI: https://doi.org/10.1016/j.jns.2019.07.007

Cell Res. 2019 Jul 31.

NDUFAB1 confers cardio-protection by enhancing mitochondrial bioenergetics through coordination of respiratory complex and supercomplex assembly.

Tingting Hou, Rufeng Zhang, Chongshu Jian, Wanqiu Ding, Yanru Wang, Shukuan Ling, Qi Ma, Xinli Hu, Heping Cheng, Xianhua Wang.

The impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is a fundamental disease mechanism in organs with a high demand for energy, including the heart. Building a more robust and safer cellular powerhouse holds the promise for protecting these organs in stressful conditions. Here, we demonstrate that NADH:ubiquinone oxidoreductase subunit AB1 (NDUFAB1), also known as mitochondrial acyl carrier protein, acts as a powerful cardio-protector by conferring greater capacity and efficiency of mitochondrial energy metabolism. In particular, NDUFAB1 not only serves as a complex I subunit, but also coordinates the assembly of respiratory complexes I, II, and III, and supercomplexes, through regulating iron-sulfur biosynthesis and complex I subunit stability. Cardiac-specific deletion of Ndufab1 in mice caused defective bioenergetics and elevated ROS levels, leading to progressive dilated cardiomyopathy and eventual heart failure and sudden death. Overexpression of Ndufab1 effectively enhanced mitochondrial bioenergetics while limiting ROS production and protected the heart against ischemia-reperfusion injury. Together, our findings identify that NDUFAB1 is a crucial regulator of mitochondrial energy and ROS metabolism through coordinating the assembly of respiratory complexes and supercomplexes, and thus provide a potential therapeutic target for the prevention and treatment of heart failure.

DOI: https://doi.org/10.1038/s41422-019-0208-x

Clin Exp Ophthalmol. 2019 Jul 31.

Mitochondrial DNA 13513G>A mutation presenting with Leber's hereditary optic neuropathy.

Benson S Chen, Valérie Biousse, Nancy J Newman.

Keywords: Genetic analysis; Leber's hereditary optic neuropathy; Mitochondrial DNA

DOI: https://doi.org/10.1111/ceo.13603

Trends Cell Biol. 2019 Jul 26. pii: S0962-8924(19)30119-9. [Epub ahead of print]

Beyond ER: Regulating TOM-Complex-Mediated Import by Ubx2.

Mohamed A Eldeeb, Emma J MacDougall, Mohamed A Ragheb, Edward A Fon.

Despite the progress in understanding the molecular responses to mitochondrial damage, responses to aberrant accumulation of mitochondrial precursor proteins and mitochondrial import defects remain poorly understood. Recent work (Mårtensson et al., Nature, 2019) has unveiled a pathway similar to endoplasmic-reticulum-associated degradation (ERAD) in fine-tuning the fidelity of translocase of the outer mitochondrial membrane (TOM) complex-mediated mitochondrial import.

Keywords: TOM complex; mitochondrial import; mitochondrial quality control; proteasome; protein degradation; protein quality control; ubiquitin

DOI: https://doi.org/10.1016/j.tcb.2019.07.003