J Clin Neurol.  2017 Oct;13(4):359-365. 10.3988/jcn.2017.13.4.359.

Ultrastructural Changes in Skeletal Muscle of Infants with Mitochondrial Respiratory Chain Complex I Defects

Affiliations
  • 1Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam, Korea.
  • 2School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
  • 3Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
  • 4Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea.
  • 5Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea. ymleemd@yuhs.ac

Abstract

BACKGROUND AND PURPOSE
The pathogenesis of mitochondrial disease (MD) involves the disruption of cellular energy metabolism, which results from defects in the mitochondrial respiratory chain complex (MRC). We investigated whether infants with MRC I defects showed ultrastructural changes in skeletal muscle.
METHODS
Twelve infants were enrolled in this study. They were initially evaluated for unexplained neurodegenerative symptoms, myopathies, or other progressive multiorgan involvement, and underwent muscle biopsies when MD was suspected. Muscle tissue samples were subjected to biochemical enzyme assays and observation by transmission electron microscopy. We compared and analyzed the ultrastructure of skeletal muscle tissues obtained from patients with and without MRC I defects.
RESULTS
Biochemical enzyme assays confirmed the presence of MRC I defects in 7 of the 12 patients. Larger mitochondria, lipid droplets, and fused structures between the outer mitochondrial membrane and lipid droplets were observed in the skeletal muscles of patients with MRC I defects.
CONCLUSIONS
Mitochondrial functional defects in MRC I disrupt certain activities related to adenosine triphosphate synthesis that produce changes in the skeletal muscle. The ultrastructural changes observed in the infants in this study might serve as unique markers for the detection of MD.

Keyword

mitochondria; respiratory chain complex; infant; muscle pathology; ultrastructure; transmission electron microscopy

MeSH Terms

Adenosine Triphosphate
Biopsy
Electron Transport*
Energy Metabolism
Enzyme Assays
Humans
Infant*
Lipid Droplets
Microscopy, Electron, Transmission
Mitochondria
Mitochondrial Diseases
Mitochondrial Membranes
Muscle, Skeletal*
Muscular Diseases
Adenosine Triphosphate

Figure

  • Fig. 1 Transmission electron microscopy of human mitochondria in skeletal muscle. Mitochondria in muscle without (A) and with (B and C) MRC I defects. Mitochondrial size is shown in (D). Changes in the percentage area of cristae and the mitochondrial size are shown in (E). The number of mitochondria is counted in (F). The number of mitochondria per square micron was multiplied by 100 to calculate the number of filaments per 100 µm2. Scale bars indicate 100 nm. MRC: mitochondrial respiratory chain complex.

  • Fig. 2 Effects of mitochondrial dysfunction on intramyocellular lipid droplets. These are images from patients without (A and C) and with (B and D) MRC I defects. Arrows indicate lipid droplets. Electron tomograms are illustrated in (E). The 3D reconstruction of mitochondria and lipid droplets are shown in (F). The outer membrane of the mitochondria is shown in pink and cristae in green. Sizes of lipid droplets were presented as the mean values for 50 lipid droplets measured in each group (G). Scale bars indicate 5 µm (A and B), 2 µm (C and D), and 100 nm (E). Li: lipid droplet, M: mitochondria, MRC: mitochondrial respiratory chain complex.


Reference

1. McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002; 1:343–351. PMID: 12849395.
Article
2. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003; 348:2656–2668. PMID: 12826641.
Article
3. Finsterer J. Mitochondriopathies. Eur J Neurol. 2004; 11:163–186. PMID: 15009163.
Article
4. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, et al. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000; 15:123–134. PMID: 10649489.
Article
5. Miles L, Wong BL, Dinopoulos A, Morehart PJ, Hofmann IA, Bove KE. Investigation of children for mitochondriopathy confirms need for strict patient selection, improved morphological criteria, and better laboratory methods. Hum Pathol. 2006; 37:173–184. PMID: 16426917.
Article
6. McFarland R, Taylor RW, Turnbull DM. Mitochondrial disease--its impact, etiology, and pathology. Curr Top Dev Biol. 2007; 77:113–155. PMID: 17222702.
Article
7. Stadhouders AM, Jap PH, Winkler HP, Eppenberger HM, Wallimann T. Mitochondrial creatine kinase: a major constituent of pathological inclusions seen in mitochondrial myopathies. Proc Natl Acad Sci U S A. 1994; 91:5089–5093. PMID: 8197190.
Article
8. Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta. 1994; 228:35–51. PMID: 7955428.
Article
9. Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002; 59:1406–1411. PMID: 12427892.
Article
10. Duman JG, Pathak NJ, Ladinsky MS, McDonald KL, Forte JG. Three-dimensional reconstruction of cytoplasmic membrane networks in parietal cells. J Cell Sci. 2002; 115:1251–1258. PMID: 11884524.
Article
11. Mun JY, Lee TH, Kim JH, Yoo BH, Bahk YY, Koo HS, et al. Caenorhabditis elegans mitofilin homologs control the morphology of mitochondrial cristae and influence reproduction and physiology. J Cell Physiol. 2010; 224:748–756. PMID: 20578245.
Article
12. Chow CW, Thorburn DR. Morphological correlates of mitochondrial dysfunction in children. Hum Reprod. 2000; 15(Suppl 2):68–78.
Article
13. Wang X, Li H, Zheng A, Yang L, Liu J, Chen C, et al. Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate. Cell Death Dis. 2014; 11. [Epub]. DOI: 10.1038/cddis.2014.473.
Article
14. Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A. 2008; 105:7070–7075. PMID: 18443288.
Article
15. Safiulina D, Veksler V, Zharkovsky A, Kaasik A. Loss of mitochondrial membrane potential is associated with increase in mitochondrial volume: physiological role in neurones. J Cell Physiol. 2006; 206:347–353. PMID: 16110491.
Article
16. Kaasik A, Safiulina D, Zharkovsky A, Veksler V. Regulation of mitochondrial matrix volume. Am J Physiol Cell Physiol. 2007; 292:C157–C163. PMID: 16870828.
Article
17. Petit PX, Goubern M, Diolez P, Susin SA, Zamzami N, Kroemer G. Disruption of the outer mitochondrial membrane as a result of large amplitude swelling: the impact of irreversible permeability transition. FEBS Lett. 1998; 426:111–116. PMID: 9598989.
Article
18. John GB, Shang Y, Li L, Renken C, Mannella CA, Selker JM, et al. The mitochondrial inner membrane protein mitofilin controls cristae morphology. Mol Biol Cell. 2005; 16:1543–1554. PMID: 15647377.
Article
19. Zick M, Rabl R, Reichert AS. Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta. 2009; 1793:5–19. PMID: 18620004.
Article
20. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013; 155:160–171. PMID: 24055366.
Article
21. Vogel F, Bornhövd C, Neupert W, Reichert AS. Dynamic subcompartmentalization of the mitochondrial inner membrane. J Cell Biol. 2006; 175:237–247. PMID: 17043137.
Article
22. Arselin G, Vaillier J, Salin B, Schaeffer J, Giraud MF, Dautant A, et al. The modulation in subunits e and g amounts of yeast ATP synthase modifies mitochondrial cristae morphology. J Biol Chem. 2004; 279:40392–40399. PMID: 15262977.
Article
23. Bustos DM, Velours J. The modification of the conserved GXXXG motif of the membrane-spanning segment of subunit g destabilizes the supramolecular species of yeast ATP synthase. J Biol Chem. 2005; 280:29004–29010. PMID: 15970598.
Article
24. Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, et al. The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J. 2002; 21:221–230. PMID: 11823415.
Article
25. von der Malsburg K, Müller JM, Bohnert M, Oeljeklaus S, Kwiatkowska P, Becker T, et al. Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis. Dev Cell. 2011; 21:694–707. PMID: 21944719.
26. Acehan D, Xu Y, Stokes DL, Schlame M. Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography. Lab Invest. 2007; 87:40–48. PMID: 17043667.
Article
27. Mannella CA. Structure and dynamics of the mitochondrial inner membrane cristae. Biochim Biophys Acta. 2006; 1763:542–548. PMID: 16730811.
Article
28. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell. 2002; 2:55–67. PMID: 11782314.
Article
29. Ding WX, Li M, Biazik JM, Morgan DG, Guo F, Ni HM, et al. Electron microscopic analysis of a spherical mitochondrial structure. J Biol Chem. 2012; 287:42373–42378. PMID: 23093403.
Article
30. Mannella CA. Structural diversity of mitochondria: functional implications. Ann N Y Acad Sci. 2008; 1147:171–179. PMID: 19076440.
31. Vock R, Hoppeler H, Claassen H, Wu DX, Billeter R, Weber JM, et al. Design of the oxygen and substrate basis of intracellular substrate supply to mitochondria in muscle cells. J Exp Biol. 1996; 199:1689–1697. PMID: 8708576.
32. Bruno C, Bertini E, Di Rocco M, Cassandrini D, Ruffa G, De Toni T, et al. Clinical and genetic characterization of Chanarin-Dorfman syndrome. Biochem Biophys Res Commun. 2008; 369:1125–1128. PMID: 18339307.
Article
33. Harriman DG, Reed R. The incidence of lipid droplets in human skeletal muscle in neuromuscular disorders: a histochemical, electron-microscopic and freeze-etch study. J Pathol. 1972; 106:1–24. PMID: 5035736.
Article
34. Leonard JV, Schapira AH. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet. 2000; 355:299–304. PMID: 10675086.
Article
Full Text Links
  • JCN
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr