bims-cytox1 2019-01-13 papers

Issue of 2019–01–13
six papers selected by
Gavin McStay, Staffordshire University

Adv Anat Embryol Cell Biol. 2019 Jan 09.

Transmission of Dysfunctional Mitochondrial DNA and Its Implications for Mammalian Reproduction.

Mitochondrial DNA (mtDNA) encodes proteins for the electron transport chain which produces the vast majority of cellular energy. MtDNA has its own replication and transcription machinery that relies on nuclear-encoded transcription and replication factors. MtDNA is inherited in a non-Mendelian fashion as maternal-only mtDNA is passed onto the next generation. Mutation to mtDNA can cause mitochondrial dysfunction, which affects energy production and tissue and organ function. In somatic cell nuclear transfer (SCNT), there is an issue with the mixing of two populations of mtDNA, namely from the donor cell and recipient oocyte. This review focuses on the transmission of mtDNA in SCNT embryos and offspring. The transmission of donor cell mtDNA can be prevented by depleting the donor cell of its mtDNA using mtDNA depletion agents prior to SCNT. As a result, SCNT embryos harbour oocyte-only mtDNA. Moreover, culturing SCNT embryos derived from mtDNA depleted cells in media supplemented with a nuclear reprograming agent can increase the levels of expression of genes related to embryo development when compared with non-depleted cell-derived embryos. Furthermore, we have reviewed how mitochondrial supplementation in oocytes can have beneficial effects for SCNT embryos by increasing mtDNA copy number and the levels of expression of genes involved in energy production and decreasing the levels of expression of genes involved in embryonic cell death. Notably, there are beneficial effects of mtDNA supplementation over the use of nuclear reprograming agents in terms of regulating gene expression in embryos. Taken together, manipulating mtDNA in donor cells and/or oocytes prior to SCNT could enhance embryo production efficiency.

Keywords: Embryo; Mitochondrial DNA; Mitochondrial supplementation; Replication; Somatic cell nuclear transfer; Transmission

DOI: https://doi.org/10.1007/102_2018_3

Mol Genet Genomic Med. 2019 Jan 08. e541

Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias.

Shanshan Zhong, Shumeng Wen, Yusen Qiu, Yanyan Yu, Ling Xin, Yang He, Xuguang Gao, Hezhi Fang, Daojun Hong, Jun Zhang.

BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients.
METHODS: The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis.
RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified.
CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.

Keywords: bilateral striatal necrosis; homoplasmy; mitochondrial DNA mutation; sex bias

DOI: https://doi.org/10.1002/mgg3.541

Nat Rev Mol Cell Biol. 2019 Jan 09.

Mitochondrial proteins: from biogenesis to functional networks.

Nikolaus Pfanner, Bettina Warscheid, Nils Wiedemann.

Mitochondria are essential for the viability of eukaryotic cells as they perform crucial functions in bioenergetics, metabolism and signalling and have been associated with numerous diseases. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. In this Review, we discuss the emerging role of the mitochondrial protein import machinery as a key organizer of these mitochondrial protein networks. The preprotein translocases that reside on the mitochondrial membranes not only function during organelle biogenesis to deliver newly synthesized proteins to their final mitochondrial destination but also cooperate with numerous other mitochondrial protein complexes that perform a wide range of functions. Moreover, these protein networks form membrane contact sites, for example, with the endoplasmic reticulum, that are key for integration of mitochondria with cellular function, and defects in protein import can lead to diseases.

DOI: https://doi.org/10.1038/s41580-018-0092-0

Biochem J. 2019 Jan 07. 476(1): 25-37

Strangers in strange lands: mitochondrial proteins found at extra-mitochondrial locations.

David P Scanlon, Michael W Salter.

The mitochondrial proteome is estimated to contain ∼1100 proteins, the vast majority of which are nuclear-encoded, with only 13 proteins encoded by the mitochondrial genome. The import of these nuclear-encoded proteins into mitochondria was widely believed to be unidirectional, but recent discoveries have revealed that many these 'mitochondrial' proteins are exported, and have extra-mitochondrial activities divergent from their mitochondrial function. Surprisingly, three of the exported proteins discovered thus far are mitochondrially encoded and have significantly different extra-mitochondrial roles than those performed within the mitochondrion. In this review, we will detail the wide variety of proteins once thought to only reside within mitochondria, but now known to 'emigrate' from mitochondria in order to attain 'dual citizenship', present both within mitochondria and elsewhere.

Keywords: cellular localisation; mitochondria; mtDNA; multifunctional proteins; trafficking; transport

DOI: https://doi.org/10.1042/BCJ20180473

Evol Bioinform Online. 2018 ;14 1176934318819835

NommPred: Prediction of Mitochondrial and Mitochondrion-Related Organelle Proteins of Nonmodel Organisms.

Keitaro Kume, Toshiyuki Amagasa, Tetsuo Hashimoto, Hiroyuki Kitagawa.

To estimate the functions of mitochondria of diverse eukaryotic nonmodel organisms in which the mitochondrial proteomes are not available, it is necessary to predict the protein sequence features of the mitochondrial proteins computationally. Various prediction methods that are trained using the proteins of model organisms belonging particularly to animals, plants, and fungi exist. However, such methods may not be suitable for predicting the proteins derived from nonmodel organisms because the sequence features of the mitochondrial proteins of diversified nonmodel organisms can differ from those of model organisms that are present only in restricted parts of the tree of eukaryotes. Here, we proposed NommPred, which predicts the mitochondrial proteins of nonmodel organisms that are widely distributed over eukaryotes. We used a gradient boosting machine to develop 2 predictors-one for predicting the proteins of mitochondria and the other for predicting the proteins of mitochondrion-related organelles that are highly reduced mitochondria. The performance of both predictors was found to be better than that of the best method available.

Keywords: gradient boosting machine; machine learning; mitochondrial proteins; mitochondrion-related organelle proteins; nonmodel organisms

DOI: https://doi.org/10.1177/1176934318819835

Proc Natl Acad Sci U S A. 2019 Jan 11. pii: 201821192. [Epub ahead of print]

Paternal comeback in mitochondrial DNA inheritance.

John Vissing.

DOI: https://doi.org/10.1073/pnas.1821192116