bims-cytox1 2021-10-31 papers

Issue of 2021–10–31
four papers selected by
Gavin McStay, Staffordshire University

Pol J Pathol. 2021 ;pii: 45313. [Epub ahead of print]72(2): 185-189

Adult-onset, isolated respiratory chain complex-IV deficiency with mild manifestations.

Isolated respiratory chain complex-IV deficiency (ICIVD) usually manifests clinically as an early-onset, severe, multisystem mitochondrial disorder (MID) and only rarely with mild manifestations. Here we present an adult patient with late onset ICIVD with slowly progressive, mild clinical manifestations. In a 57-years old Caucasian male with exercise-induced myalgia, muscle cramps, ptosis, and recurrent creatine-kinase (CK) elevation, muscle biopsy and biochemical investigations of the left lateral vastus muscle revealed ICIVD. He additionally had developed diabetes, arterial hypertension, hyperlipidemia, retinal detachment, transient hypothyroidism, and a hearing fall. The family history was positive for diabetes, Parkinsonism, and dementia in the mother and myopathy in the brother, suggesting maternal transmission of the MID. Conclusions: ICIVD may manifest in adulthood with only mild manifestations and may take a slowly progressive course. Patients with mild hyper-CKemia and mild multisystem manifestations, including the muscle, profit from muscle biopsy and biochemical investigations.

Keywords: mitochondrial; multisystem; myopathy.; respiratory chain; mtDNA

DOI: https://doi.org/10.5114/pjp.2021.109523

J Biochem. 2021 Oct 26. pii: mvab118. [Epub ahead of print]

Crystallographic studies of cytochrome c and cytochrome c oxidase.

Tomitake Tsukihara.

I started on crystallographic studies of cytochrome c (Cyt.c) in the later 1960s at Institute for Protein Research, Osaka University. The institute successfully built the structural model of ferro-Cyt.c by the multiple heavy atom replacement method in the early 1970s. In the early 1990s, crystals of cytochrome c oxidase (CcO) from bovine heart were obtained by using polyethylene glycol 4000 (Sigma) as the precipitant. We reported the first structure of a mammalian membrane protein at 2.8 Å resolution in 1995. High-resolution crystallography of CcO is in progress to understand the coupling mechanism of O2 reduction and proton pumping. We determined the structure of the mammalian Cyt.c-CcO complex at 2.0 Å resolution and identified the "soft and specific" interaction between Cyt.c and CcO, which effected high-efficiency inter-molecular electron transfer.

DOI: https://doi.org/10.1093/jb/mvab118

Dev Cell. 2021 Oct 22. pii: S1534-5807(21)00809-1. [Epub ahead of print]

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.

Shefali Krishna, Rafael Arrojo E Drigo, Juliana S Capitanio, Ranjan Ramachandra, Mark Ellisman, Martin W Hetzer.

In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.

Keywords: age mosaicism; aging; electron transport chain; heterogeneity; long-lived proteins; mitochondria; muscle; neurons; protein homeostasis; supercomplexes

DOI: https://doi.org/10.1016/j.devcel.2021.10.008

Ann Neurol. 2021 Oct 30.

The Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.

Albert Z Lim, Yi Shiau Ng, Alasdair Blain, Cecilia Jiminez-Moreno, Charlotte L Alston, Victoria Nesbitt, Louise Simmons, Saikat Santra, Evangeline Wassmer, Emma L Blakely, Doug M Turnbull, Robert W Taylor, Gráinne S Gorman, Robert McFarland.

OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates and identify factors that may determine the disease course of Leigh syndrome.
METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scales (NPMDS) at baseline 3.7 years (IQR 2.0-7.6) and follow-up assessments 7.5 years (IQR 3.7-11.0) in clinics were enrolled. 82% of this cohort had a confirmed genetic diagnosis with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25) and severe (>25) disease burden. Detailed clinical, neuroradiological and molecular genetic findings were also analysed.
RESULTS: The median total NPMDS scores rose significantly (Z=-6.9, p<0.001) and the percentage of children with severe disease burden doubled (22%→42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding and education) and extrapyramidal features contributed significantly to the disease burden (τb ≈0.45-0.68, p<0.001). These children also deteriorated to wheelchair dependence (31%→57%), exclusive enteral feeding (22%→46%) and one-to-one assistance for self-care (25%→43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden) (p<0.001) and steeper increase in NPMDS score per annum (disease progression) (p<0.001). Other predictors of poor outcomes include SURF1 gene variants (p<0.001) and bilateral caudate changes on neuroimaging (p<0.01).
INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26260