Groennebaek 2020 Cells

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Groennebaek T, Billeskov TB, Schytz CT, Jespersen NR, Bøtker HE, Olsen RKJ, Eldrup N, Nielsen J, Farup J, De Paoli FV, Vissing K (2020) Mitochondrial structure and function in the metabolic myopathy accompanying patients with critical limb ischemia. Cells 9:E570.

» PMID: 32121096 Open Access

Groennebaek T, Billeskov TB, Schytz CT, Jespersen NR, Boetker HE, Olsen RKJ, Eldrup N, Nielsen J, Farup J, De Paoli FV, Vissing K (2020) Cells

Abstract: Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (β-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.

Keywords: Bioenergetics, Biomarkers, Mitochondria, Myopathy, Peripheral artery disease, Ultrastructure Bioblast editor: Plangger M O2k-Network Lab: DK Aarhus Boetker HE


Labels: MiParea: Respiration, mt-Structure;fission;fusion, Patients  Pathology: Myopathy  Stress:Ischemia-reperfusion  Organism: Human  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, OXPHOS  Pathway: N, NS, ROX  HRR: Oxygraph-2k 

Labels, 2020-03