bims-cytox1 2022-01-16 papers

Issue of 2022–01–16
five papers selected by
Gavin McStay, Staffordshire University

Front Cell Dev Biol. 2021 ;9 803205

Targeting and Insertion of Membrane Proteins in Mitochondria.

Mitochondrial membrane proteins play an essential role in all major mitochondrial functions. The respiratory complexes of the inner membrane are key for the generation of energy. The carrier proteins for the influx/efflux of essential metabolites to/from the matrix. Many other inner membrane proteins play critical roles in the import and processing of nuclear encoded proteins (∼99% of all mitochondrial proteins). The outer membrane provides another lipidic barrier to nuclear-encoded protein translocation and is home to many proteins involved in the import process, maintenance of ionic balance, as well as the assembly of outer membrane components. While many aspects of the import and assembly pathways of mitochondrial membrane proteins have been elucidated, many open questions remain, especially surrounding the assembly of the respiratory complexes where certain highly hydrophobic subunits are encoded by the mitochondrial DNA and synthesised and inserted into the membrane from the matrix side. This review will examine the various assembly pathways for inner and outer mitochondrial membrane proteins while discussing the most recent structural and biochemical data examining the biogenesis process.

Keywords: assembly; membrane proteins; mitochondria; mitochondrial chaperones; translocons

DOI: https://doi.org/10.3389/fcell.2021.803205

Int J Mol Sci. 2021 Dec 25. pii: 210. [Epub ahead of print]23(1):

Mitochondrial Retinopathies.

Massimo Zeviani, Valerio Carelli.

The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns-Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.

Keywords: Kearns-Sayre syndrome; Leber’s hereditary optic neuropathy (LHON); ataxia and retinitis pigmentosa (NARP); autosomal dominant optic atrophy (ADOA); mitochondrial DNA; mitochondrial disorders; mtDNA heteroplasmic deletions; neurogenic muscle weakness; optic atrophy; retina; retinitis pigmentosa

DOI: https://doi.org/10.3390/ijms23010210

Int J Mol Sci. 2021 Dec 21. pii: 7. [Epub ahead of print]23(1):

Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.

Anna M Lenkiewicz, Magda Krakowczyk, Piotr Bragoszewski.

With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

Keywords: mitochondrial biogenesis; molecular chaperone; proteasome; protein degradation; protein precursor; protein transport; proteostasis; quality control; ubiquitin

DOI: https://doi.org/10.3390/ijms23010007

Front Cell Dev Biol. 2021 ;9 767407

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.

Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello.

In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband's overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband's neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.

Keywords: combined oxidative phosphorylation deficiency; leigh syndrome; metabolic adaptability; mitochondrial energy metabolism; nuclear variants; whole exome sequencing

DOI: https://doi.org/10.3389/fcell.2021.767407

Biomed Opt Express. 2021 Dec 01. 12(12): 7632-7656

Quantification of cytochrome c oxidase and tissue oxygenation using CW-NIRS in a mouse cerebral cortex.

Mada Hashem, Ying Wu, Jeff F Dunn.

We provide a protocol for measuring the absolute concentration of the oxidized and reduced state of cytochrome c oxidase (CCO) in the cerebral cortex of mice, using broadband continuous-wave NIRS. The algorithm (NIR-AQUA) allows for absolute quantification of CCO and deoxyhemoglobin. Combined with an anoxia pulse, this also allows for quantification of total hemoglobin, and tissue oxygen saturation. CCO in the cortex was 4.9 ± 0.1 μM (mean ± SD, n=6). In normoxia, 84% of CCO was oxidized. We include hypoxia and cyanide validation studies to show CCO can be quantified independently to hemoglobin. This can be applied to study oxidative metabolism in the many rodent models of neurological disease.

DOI: https://doi.org/10.1364/BOE.435532