bims-cytox1 2020-06-14 papers

Issue of 2020‒06‒14
five papers selected by
Gavin McStay
Staffordshire University

EMBO J. 2020 Jun 08. e103912

Multiple pathways coordinate assembly of human mitochondrial complex IV and stabilization of respiratory supercomplexes.

Teresa Lobo-Jarne, Rafael Pérez-Pérez, Flavia Fontanesi, Alba Timón-Gómez, Ilka Wittig, Ana Peñas, Pablo Serrano-Lorenzo, Inés García-Consuegra, Joaquín Arenas, Miguel A Martín, Antoni Barrientos, Cristina Ugalde.

Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with pleiotropic complex I defects. Using complexome profiling and biochemical analyses, we have explored the structural rearrangements of the respiratory chain in human cell lines depleted of the catalytic complex IV subunit COX1 or COX2. In the absence of a functional complex IV holoenzyme, several supercomplex I+III2 species coexist, which differ in their content of COX subunits and COX7A2L/HIGD2A assembly factors. The incorporation of an atypical COX1-HIGD2A submodule attenuates supercomplex I+III2 turnover rate, indicating an unexpected molecular adaptation for supercomplexes stabilization that relies on the presence of COX1 independently of holo-complex IV formation. Our data set the basis for complex I structural dependence on complex IV, revealing the co-existence of alternative pathways for the biogenesis of "supercomplex-associated" versus individual complex IV, which could determine physiological adaptations under different stress and disease scenarios.

Keywords: mitochondrial biogenesis; mitochondrial complex IV assembly; mitochondrial respiratory chain; respirasomes; respiratory supercomplex stabilization

DOI: https://doi.org/10.15252/embj.2019103912

J Clin Invest. 2020 Jun 09. pii: 134965. [Epub ahead of print]

PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy.

Jialing Yu, Xiaoyang Liang, Yanchun Ji, Cheng Ai, Junxia Liu, Ling Zhu, Zhipeng Nie, Xiaofen Jin, Chenghui Wang, Juanjuan Zhang, Fuxin Zhao, Shuang Mei, Xiaoxu Zhao, Xiangtian Zhou, Minglian Zhang, Meng Wang, Taosheng Huang, Pingping Jiang, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole exome sequencing, we identified the X-linked LHON modifier (c.157C>T, p. Arg53Trp) in the PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in three Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited the defective assembly, stability and function of ATP synthase, verified by PRICKLE3 knock-down cells. Co-immunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, mutant cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunctions than those carrying only single mutation. These indicated that the p.Arg53Trp mutation acted in synergy with m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3 deficient mice exhibited the pronounced ATPase deficiencies. Prickle3 knock-out mice recapitulated LHON phenotypes with retina deficiencies including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into pathophysiology of LHON that were manifested by interaction between mtDNA mutation and X-linked nuclear modifier.

Keywords: Genetic diseases; Genetics; Mitochondria; Molecular pathology; Ophthalmology

DOI: https://doi.org/10.1172/JCI134965

Graefes Arch Clin Exp Ophthalmol. 2020 Jun 07.

Genotypic and phenotypic characteristics of Korean children with childhood-onset Leber's hereditary optic neuropathy.

Ye Jin Ahn, Yooyeon Park, Sun Young Shin, Hyojin Chae, Myungshin Kim, Shin Hae Park.

PURPOSE: We sought to identify the phenotypic and genotypic characteristics of Korean children with genetically confirmed Leber's hereditary optic neuropathy (LHON).METHODS: The medical records of 64 genetically confirmed LHON patients were reviewed. Seventeen patients aged 13 years or younger with optic atrophy with positive mitochondrial DNA (mtDNA) mutations were considered to demonstrate childhood-onset LHON. The non-childhood-onset group included 47 patients with genetically confirmed LHON who experienced disease onset later than 13 years of age. The type of mtDNA mutation, visual acuity (VA), color vision, fundus photography, retinal nerve fiber layer (RNFL) thickness, and visual field were investigated.
RESULTS: Sequence analysis of the mitochondrial genome revealed five different kinds of LHON-associated mtDNA mutations among our childhood-onset patients, including m.11778G>A (58.8%), m.3496G>T (11.8%), m.3497C>T (5.9%), m.11696G>A (5.9%), and m.14502T>C (5.9%). The mean final best-corrected VA in the childhood-onset group was better than that in the non-childhood-onset group with the value of logMAR 0.29 (0.09-0.75) vs. 0.55 (0.27-1.29) (expressed as median (interquartile range); p = 0.05). Spontaneous visual recovery was observed in 35.3% of the childhood-onset group but in only 12.8% of the non-childhood-onset group (p = 0.04). Eight patients (47.1%) showed interocular asymmetry of the disease, with two presenting true unilateral involvement of the optic nerve and the other six patients demonstrating unilateral subclinical manifestations with bilateral optic atrophy.
CONCLUSION: Involvement of secondary mitochondrial mutations was confirmed in patients with childhood-onset LHON. Characteristic clinical features of childhood-onset LHON included a higher proportion of subacute or insidious onset of symptoms, better VA, higher spontaneous recovery, and asymmetrical ocular involvement.

Keywords: Childhood; Leber’s hereditary optic neuropathy; Mitochondrial DNA mutation

DOI: https://doi.org/10.1007/s00417-020-04757-x

Front Physiol. 2020 ;11 515

Mitochondrial Quality Control and Cellular Proteostasis: Two Sides of the Same Coin.

Justin M Quiles, Åsa B Gustafsson.

Mitochondrial dysfunction is a hallmark of cardiac pathophysiology. Defects in mitochondrial performance disrupt contractile function, overwhelm myocytes with reactive oxygen species (ROS), and transform these cellular powerhouses into pro-death organelles. Thus, quality control (QC) pathways aimed at identifying and removing damaged mitochondrial proteins, components, or entire mitochondria are crucial processes in post-mitotic cells such as cardiac myocytes. Almost all of the mitochondrial proteins are encoded by the nuclear genome and the trafficking of these nuclear-encoded proteins necessitates significant cross-talk with the cytosolic protein QC machinery to ensure that only functional proteins are delivered to the mitochondria. Within the organelle, mitochondria contain their own protein QC system consisting of chaperones and proteases. This system represents another level of QC to promote mitochondrial protein folding and prevent aggregation. If this system is overwhelmed, a conserved transcriptional response known as the mitochondrial unfolded protein response is activated to increase the expression of proteins involved in restoring mitochondrial proteostasis. If the mitochondrion is beyond repair, the entire organelle must be removed before it becomes cytotoxic and causes cellular damage. Recent evidence has also uncovered mitochondria as participants in cytosolic protein QC where misfolded cytosolic proteins can be imported and degraded inside mitochondria. However, this process also places increased pressure on mitochondrial QC pathways to ensure that the imported proteins do not cause mitochondrial dysfunction. This review is focused on discussing the pathways involved in regulating mitochondrial QC and their relationship to cellular proteostasis and mitochondrial health in the heart.

Keywords: Parkin; UPR; UPS; import; mitochondria; mitophagy; proteasome; proteotoxicity

DOI: https://doi.org/10.3389/fphys.2020.00515