Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis

Crugnola, V.; Lamperti, Costanza; Lucchini, Valeria; Ronchi, Dario; Peverelli, Lorenzo; Prelle, A.; Sciacco, Monica; Bordoni, Andreina; Fassone, Elisa; Fortunato, Francesco; Corti, Stefania; Silani, Vincenzo; Bresolin, Nereo; Mauro, Salvatore Di; Comi, Giacomo P.; Moggio, Maurizio

doi:10.1001/archneurol.2010.128

Cited by 130 publications

(92 citation statements)

References 54 publications

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“…*, p Ͻ 0.05; **, p Ͻ 0.01. E, oxygen consumption rates of the myotubes were analyzed on day 7 in the absence (Basal) or presence of 2.5 g/ml oligomycin (Oligo) and a 1. by atrophy and mitochondrial dysfunction (66,67). PERM1 followed a similar pattern of induction by exercise and suppression in ALS patients, suggesting that the regulatory pathways seen in C2C12 cells reflect ones that are active in human exercise physiology and in the pathophysiology of neuromuscular disorders.…”

Section: Discussionmentioning

confidence: 77%

Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1)- and Estrogen-related Receptor (ERR)-induced Regulator in Muscle 1 (PERM1) Is a Tissue-specific Regulator of Oxidative Capacity in Skeletal Muscle Cells

Cho

Hazen

Russell

et al. 2013

Journal of Biological Chemistry

105

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Background:The regulatory mechanisms that control skeletal muscle bioenergetics are not fully understood. Results: The muscle-specific protein Perm1 is induced by exercise and exercise-activated regulators and controls the expression of energy homeostasis genes. Conclusion: Perm1 is a regulator of mitochondrial oxidative capacity and bioenergetics. Significance: Novel muscle regulators of bioenergetics may facilitate approaches for preserving/enhancing muscle function.

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Section: Discussionmentioning

confidence: 77%

Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1)- and Estrogen-related Receptor (ERR)-induced Regulator in Muscle 1 (PERM1) Is a Tissue-specific Regulator of Oxidative Capacity in Skeletal Muscle Cells

Cho

Hazen

Russell

et al. 2013

Journal of Biological Chemistry

105

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“…[193]). The protein amount of several marker enzymes can also be evaluated using histochemical staining of tissue preparations, including nicotinamide adenine dinucleotide tetrazolium reductase [201], cytochrome c oxidase [202] and succinate dehydrogenase [203,204].…”

Section: Biochemical Biomarkersmentioning

confidence: 99%

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

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Running title: Regulation and quantification of mitochondrial morphology and content. Word count: 15,454 (total)Characters: 107,091 (including spaces); 92,067 (excluding spaces) Keywords: mitochondrial biogenesis, mitochondrial dynamics, mitochondrial degradation, living cells, TMRM, microscopy, segmentation, image analysis.Page 2 of 37 ABSTRACTMitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

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“…This technique, with early studies dating back to 1968, remains popular, with many considering it the "gold standard" for identifying mitochondrial diseases in patients 14,19,26,27 . It is now frequently used to investigate mtDNA mutation-driven aging and aging-related disorders 12,13,18,20,21,24 . The COX/SDH double-labeling method is often used in parallel with other techniques to identify specific mtDNA mutations and to further investigate the mitochondrial respiratory enzymes, such as oximetric measurements and spectrophotometric enzyme analysis 28,29 .…”

Section: Figure 1 Mitochondrial Respiratory Complexes I-vmentioning

confidence: 99%

Visualization of Mitochondrial Respiratory Function using Cytochrome <em>C</em> Oxidase / Succinate Dehydrogenase (COX/SDH) Double-labeling Histochemistry

Ross

2011

JoVE

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Mitochondrial DNA (mtDNA) defects are an important cause of disease and may underlie aging and aging-related alterations 1,2 . The mitochondrial theory of aging suggests a role for mtDNA mutations, which can alter bioenergetics homeostasis and cellular function, in the aging process 3 . A wealth of evidence has been compiled in support of this theory 1,4 , an example being the mtDNA mutator mouse 5 ; however, the precise role of mtDNA damage in aging is not entirely understood 6,7 .Observing the activity of respiratory enzymes is a straightforward approach for investigating mitochondrial dysfunction. Complex IV, or cytochrome c oxidase (COX), is essential for mitochondrial function. The catalytic subunits of COX are encoded by mtDNA and are essential for assembly of the complex (Figure 1). Thus, proper synthesis and function are largely based on mtDNA integrity 2 . Although other respiratory complexes could be investigated, Complexes IV and II are the most amenable to histochemical examination 8,9 . Complex II, or succinate dehydrogenase (SDH), is entirely encoded by nuclear DNA (Figure 1), and its activity is typically not affected by impaired mtDNA, although an increase might indicate mitochondrial biogenesis [10][11][12] . The impaired mtDNA observed in mitochondrial diseases, aging, and age-related diseases often leads to the presence of cells with low or absent COX activity 2,12-14 . Although COX and SDH activities can be investigated individually, the sequential double-labeling method 15,16 has proved to be advantageous in locating cells with mitochondrial dysfunction 12,17-21 .Many of the optimal constitutions of the assay have been determined, such as substrate concentration, electron acceptors/donors, intermediate electron carriers, influence of pH, and reaction time 9,22,23 . 3,3'-diaminobenzidine (DAB) is an effective and reliable electron donor 22 . In cells with functioning COX, the brown indamine polymer product will localize in mitochondrial cristae and saturate cells 22 . Those cells with dysfunctional COX will therefore not be saturated by the DAB product, allowing for the visualization of SDH activity by reduction of nitroblue tetrazolium (NBT), an electron acceptor, to a blue formazan end product 9,24 . Cytochrome c and sodium succinate substrates are added to normalize endogenous levels between control and diseased/mutant tissues 9 . Catalase is added as a precaution to avoid possible contaminating reactions from peroxidase activity 9,22 . Phenazine methosulfate (PMS), an intermediate electron carrier, is used in conjunction with sodium azide, a respiratory chain inhibitor, to increase the formation of the final reaction products 9,25 . Despite this information, some critical details affecting the result of this seemly straightforward assay, in addition to specificity controls and advances in the technique, have not yet been presented. Video LinkThe video component of this article can be found at

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Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis

Cited by 130 publications

References 54 publications

Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1)- and Estrogen-related Receptor (ERR)-induced Regulator in Muscle 1 (PERM1) Is a Tissue-specific Regulator of Oxidative Capacity in Skeletal Muscle Cells

Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1)- and Estrogen-related Receptor (ERR)-induced Regulator in Muscle 1 (PERM1) Is a Tissue-specific Regulator of Oxidative Capacity in Skeletal Muscle Cells

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Visualization of Mitochondrial Respiratory Function using Cytochrome <em>C</em> Oxidase / Succinate Dehydrogenase (COX/SDH) Double-labeling Histochemistry

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