Mitochondrial disorders are heterogeneous multisystemic disorders due to impaired oxidative phosphorylation causing defective mitochondrial energy production. Common histological hallmarks of mitochondrial disorders are RRFs (ragged red fibres), muscle fibres with abnormal focal accumulations of mitochondria. In contrast with the growing understanding of the genetic basis of mitochondrial disorders, the fate of phenotypically affected muscle fibres remains largely unknown. We investigated PCD (programmed cell death) in muscle of 17 patients with mitochondrial respiratory chain dysfunction. We documented that in affected muscle fibres, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1 (apoptotic protease-activating factor 1), caspase 9 that, in turn, activates effector caspase 3, caspase 6, and caspase 7, suggesting the execution of the intrinsic apoptotic pathway. Whereas active caspase 3 underwent nuclear translocation, AIF (apoptosis-inducing factor) mainly stayed within mitochondria, into which an up-regulated Bax is relocated. The significant increase in caspase 2, caspase 3 and caspase 6 activity strongly suggest that the cell death programme is caspase-dependent and the activation of caspase 2 together with PUMA (p53 up-regulated modulator of apoptosis) up-regulation point to a role for oxidative stress in triggering the intrinsic pathway. Concurrently, in muscle of patients, the number of satellite cells was significantly increased and myonuclei were detected at different stages of myogenic differentiation, indicating that a reparative programme is ongoing in muscle of patients with mitochondrial disorders. Together, these data suggest that, in patients with mitochondrial disorders, affected muscle fibres are trapped in a mitochondria-regulated caspase-dependent PCD while repairing events take place.
Skip Nav Destination
Article navigation
February 2016
-
Cover Image
Cover Image
Image modified from a figure representing the 5 mechanisms of annexin A1 externalization through non-classic secretory pathways, discussed by Boudhraa et al in issue 130(4) of Clinical Science. For further details please see pp. 205–220. Image kindly provided by Z. Boudhraa, B. Bouchon, C. Viallard, M. D'Incan and F. Degoul.
Research Article|
December 17 2015
Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders
Valeria Guglielmi;
Valeria Guglielmi
1
*Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Gaetano Vattemi;
Gaetano Vattemi
1
*Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy
Correspondence: Associate Professor Gaetano Vattemi (email [email protected]).
Search for other works by this author on:
Roberto Chignola;
Roberto Chignola
†Department of Biotechnology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Anna Chiarini;
Anna Chiarini
‡Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Matteo Marini;
Matteo Marini
*Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Ilaria Dal Prà;
Ilaria Dal Prà
‡Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Marzia Di Chio;
Marzia Di Chio
§Department of Public Health and Community Medicine, Section of Pharmacology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Cristiano Chiamulera;
Cristiano Chiamulera
§Department of Public Health and Community Medicine, Section of Pharmacology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Ubaldo Armato;
Ubaldo Armato
‡Department of Life and Reproduction Sciences, Section of Histology and Embryology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Giuliano Tomelleri
Giuliano Tomelleri
*Department of Neurological and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
June 03 2015
Revision Received:
October 06 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (3): 167–181.
Article history
Received:
June 03 2015
Revision Received:
October 06 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Citation
Valeria Guglielmi, Gaetano Vattemi, Roberto Chignola, Anna Chiarini, Matteo Marini, Ilaria Dal Prà, Marzia Di Chio, Cristiano Chiamulera, Ubaldo Armato, Giuliano Tomelleri; Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders. Clin Sci (Lond) 1 February 2016; 130 (3): 167–181. doi: https://doi.org/10.1042/CS20150394
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Cited By
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |