bims-cytox1 2019-10-13 papers

Issue of 2019‒10‒13
four papers selected by
Gavin McStay
Staffordshire University

Plant Physiol. 2019 Oct 10. pii: pp.00822.2019. [Epub ahead of print]

A Mitochondrial LYR Protein is Required for Complex I Assembly.

Aneta Ivanova, Mabel Gill-Hille, Shaobai Huang, Rui Branca, Beata Kmiec, Pedro F Teixeira, Janne Lehtiö, James Whelan, Monika W Murcha.

Complex I biogenesis requires the expression of both nuclear and mitochondrial genes, the, import of proteins, co-factor biosynthesis, and the assembly of at least 49 individual subunits. Assembly factors interact with subunits of Complex I but are not part of the final holocomplex. We show that in Arabidopsis (Arabidopsis thaliana), a mitochondrial matrix protein (EMB1793, At1g76060), which we term COMPLEX I ASSEMBLY FACTOR 1 (CIAF1), contains a LYR domain and is required for Complex I assembly. T DNA insertion mutants of CIAF1 lack Complex I and the Supercomplex I+III. Biochemical characterisation shows that the assembly of Complex I is stalled at 650 and 800 kDa intermediates in mitochondria isolated from ciaf1 mutant lines.I. Yeast-two-hybrid interaction and complementation assays indicate that CIAF1 specifically interacts with the 23-kDa TYKY-1 matrix domain subunit of Complex I and likely plays a role in Fe-S insertion into this subunit. These data show that CIAF1 plays an essential role in assembling the peripheral matrix arm Complex I subunits into the Complex I holoenzyme.

DOI: https://doi.org/10.1104/pp.19.00822

Adv Ther. 2019 Oct 11.

Leber's Hereditary Optic Neuropathy as a Promising Disease for Gene Therapy Development.

Cuneyt Karaarslan.

Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.

Keywords: Gene therapy; Genes; Leber’s hereditary optic neuropathy; Mutation

DOI: https://doi.org/10.1007/s12325-019-01113-2

J Biol Chem. 2019 Oct 07. pii: jbc.RA119.010317. [Epub ahead of print]

Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV.

Ngoc H Hoang, Vera Strogolova, Jaramys J Mosley, Rosemary A Stuart, Jonathan Hosler.

Hypoxia-inducible gene domain 1 (HIGD1) proteins are small integral membrane proteins, conserved from bacteria to humans, that associate with oxidative phosphorylation supercomplexes. Using yeast as a model organism, we have previously shown that its two HIGD1 proteins, Rcf1 and Rcf2, are required for the generation and maintenance of a normal membrane potential (Δψ) across the inner mitochondrial membrane (IMM). We have postulated that the lower Δψ observed in the absence of the HIGD1 proteins may be due to decreased proton pumping by complex IV (CIV) or to an enhanced leakage of protons across the IMM. Here, we measured the Δψ generated by complex III (CIII) to discriminate between these possibilities. First, we found that the decreased Δψ observed in the absence of the HIGD1 proteins cannot be due to decreased proton pumping by CIV, since CIII, operating alone, also exhibited a decreased Δψ when HIGD1 proteins were absent. Since CIII can neither lower its pumping stoichiometry nor transfer protons completely across the IMM, this result indicates that HIGD1 protein ablation enhances proton leakage across the IMM. Second, we demonstrate that this proton leakage occurs through CIV, since Δψ generation by CIII is restored when CIV is removed from the cell. Third, the proton leakage appeared to take place through an inactive population of CIV that accumulates when HIGD1 proteins are absent. We conclude that HIGD1 proteins in yeast prevent CIV inactivation, likely by preventing the loss of lipids bound within the Cox3 protein of CIV.

Keywords: Rcf; cytochrome c oxidase (Complex IV); hypoxia-inducible gene domain 1 (HIGD1); lipid-protein interaction; mitochondria; mitochondrial membrane potential; oxidative phosphorylation; proton leak; respiration; suicide inactivation

DOI: https://doi.org/10.1074/jbc.RA119.010317

J Exp Bot. 2019 Sep 06. pii: erz391. [Epub ahead of print]

Pentatricopeptide repeat protein DEK40 is required for mitochondrial function and kernel development in maize.

Ru Chang Ren, Xiaoduo Lu, Ya Jie Zhao, Yi Ming Wei, Li Li Wang, Lin Zhang, Wen Ting Zhang, Chunyi Zhang, Xian Sheng Zhang, Xiang Yu Zhao.

Pentatricopeptide repeat (PPR) proteins are one of the largest protein families, which consists of >400 members in most species. However, the molecular functions of many PPR proteins are still uncharacterized. Here, we isolated a maize mutant, defective kernel 40 (dek40). Positional cloning, and genetic and molecular analyses revealed that DEK40 encodes a new E+ subgroup PPR protein that is localized in the mitochondrion. DEK40 recognizes and directly binds to cox3, nad2, and nad5 transcripts and functions in their processing. In the dek40 mutant, abolishment of the C-to-U editing of cox3-314, nad2-26, and nad5-1916 leads to accumulated reactive oxygen species and promoted programmed cell death in endosperm cells due to the dysfunction of mitochondrial complexes I and IV. Furthermore, RNA sequencing analysis showed that gene expression in some pathways, such as glutathione metabolism and starch biosynthesis, was altered in the dek40 mutant compared with the wild-type control, which might be involved in abnormal development of the maize mutant kernels. Thus, our results provide solid evidence on the molecular mechanism underlying RNA editing by DEK40, and extend our understanding of PPR-E+ type protein in editing functions and kernel development in maize.

Keywords: Kernel development; RNA editing; maize; mitochondrion; pentatricopeptide repeat protein

DOI: https://doi.org/10.1093/jxb/erz391