Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition

Dubinin, Mikhail V.; Talanov, Eugeny Yu.; Tenkov, Kirill S.; Starinets, Vlada S.; Mikheeva, I. B.; Шарапов, М. Г.; Belosludtsev, Konstantin N.

doi:10.1016/j.bbadis.2020.165674

Cited by 57 publications

(74 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Morphological alterations of the mitochondria have been reported in DMD muscles with higher rates of swollen mitochondria compared with that of normal muscle 38 . PL alterations in DMD and a dysregulation of Ca 2+ homeostasis may induce mitochondrial membrane fragility and associated morphological changes with subsequent energy and oxidative metabolism disruptions [39][40][41][42] . Energy metabolism impairments in DMD are major contributors to DYS-deficient muscle degeneration 43 as illustrated by mitochondrial function improvement upon the partial restoration of DYS expression 44 .…”

Section: Discussionmentioning

confidence: 99%

Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Dabaj

Ferey

Marguet

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Dabaj

Ferey

Marguet

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Numerous mitochondrial alterations are correlated with dystrophic conditions, including impaired ATP production, substrate handling, Ca 2+ buffering capacity, and elevated ROS production. The mitochondria in muscular fibers from dystrophic mdx mice (a murine model of DMD) displayed a significantly shorter time to MPT induction in response to Ca 2+ than WT mice [155]. In C. elegans and zebrafish models of DMD, mitochondrial fragmentation is detectable before overt signs of muscular degeneration, and CsA feeding delays muscle degeneration [156].…”

Section: Ptpc In Muscular Dystrophies (Mds)mentioning

confidence: 99%

Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

et al. 2020

View full text Add to dashboard Cite

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.

show abstract

“…Destabilization of this complex from the reduction of dystrophin results in progressive muscle-fiber damage and membrane leakage (2). In addition, reduction of dystrophin causes increased sarcoplasmic calcium levels, which may cause a cascade of detrimental effects, including mitochondrial damage (3)(4)(5)(6)(7). DMD is a disorder that affects over 1 in 3,500 live male births.…”

mentioning

confidence: 99%

Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model

Ellwood

Hewitt

Torregrossa

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H2S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted H2S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H2S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H2S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H2S delivery compounds has potential as a therapeutic approach to DMD treatment.

show abstract

Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition

Cited by 57 publications

References 49 publications

Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model

Contact Info

Product

Resources

About