Mechanisms of mitochondrial DNA escape and its relationship with different metabolic diseases

Pérez-Treviño, Perla; Velasquez, Monica P. Soto; Garcı́a, Noemı́

doi:10.1016/j.bbadis.2020.165761

Cited by 93 publications

(74 citation statements)

References 115 publications

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“…MPTP and ROS can also promote the activation of mitochondrial fission and mitophagy to eliminate damaged mitochondria ( Figure 2 ). In mitochondrial fission, MAMs signal the ER tubules to encircle mitochondria and tag the sites for mitochondrial division [ 139 ]. Accordingly to mitochondrial implication in NMDs, dysregulation of MPTP opening and defective autophagy have been associated with muscular dystrophies, like collagen VI myopathies (CMD), BMD, DMD, LGMD, and DD [ 14 , 15 ] and, remarkably, most of NMDs show some level of deregulation in most of these pathways.…”

Section: Mitochondrial Pathways Altered In Nmdmentioning

confidence: 99%

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The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

2020

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Neuromuscular diseases (NMDs) are a heterogeneous group of acquired or inherited rare disorders caused by injury or dysfunction of the anterior horn cells of the spinal cord (lower motor neurons), peripheral nerves, neuromuscular junctions, or skeletal muscles leading to muscle weakness and waste. Unfortunately, most of them entail serious or even fatal consequences. The prevalence rates among NMDs range between 1 and 10 per 100,000 population, but their rarity and diversity pose difficulties for healthcare and research. Some molecular hallmarks are being explored to elucidate the mechanisms triggering disease, to set the path for further advances. In fact, in the present review we outline the metabolic alterations of NMDs, mainly focusing on the role of mitochondria. The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction. ROS burst, impaired autophagy, and increased inflammation are observed in many NMDs. Increasing knowledge of the etiology of NMDs will help to develop better diagnosis and treatments, eventually reducing the health and economic burden of NMDs for patients and healthcare systems.

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Section: Mitochondrial Pathways Altered In Nmdmentioning

confidence: 99%

“…Thus, mitochondrial DAMPs can also trigger an inflammatory response [ 128 ]. DAMPs include proteins and peptides, such as N-formyl peptides and TFAM, as well as lipids, and metabolites such as cardiolipin, succinate and ATP, and mtDNA [ 139 ].…”

Section: Mitochondrial Pathways Altered In Nmdmentioning

confidence: 99%

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

2020

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“…Only recently, it has emerged that, apart from their relevance to cellular energy provision and ROS signaling, mitochondria participate in inflammation by triggering a danger signaling response [16,17]. In particular, in response to various stressors, mitochondrial DNA (mtDNA) can be displaced into intra-or extracellular compartments [18]. Albeit the mechanisms whereby mtDNA is unloaded from mitochondria are largely unclear, several lines of evidence indicate that mtDNA can be shuttled toward the extracellular compartment via the generation and release of extracellular vesicles (EVs) [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, in response to various stressors, mitochondrial DNA (mtDNA) can be displaced into intra-or extracellular compartments [18]. Albeit the mechanisms whereby mtDNA is unloaded from mitochondria are largely unclear, several lines of evidence indicate that mtDNA can be shuttled toward the extracellular compartment via the generation and release of extracellular vesicles (EVs) [18][19][20][21]. Along with mtDNA and other mitochondrial components, cell-free intact mitochondria have been found in the blood of healthy people [21].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

et al. 2020

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Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

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“…Animal models with obesity display mitochondrial hyperacetylation, fragmentation, ROS production, and mitochondrial permeability transition pore openings with diastolic dysfunction [81][82][83]. All these changes contribute to mitochondrial DNA (mtDNA) release and systemic inflammation [84] that, in conjunction with ROS, are inflammasome activators involved in heart inflammation [85]. As a result, IL-18 secretion may induce fibrosis and cardiac hypertrophy resulting in diastolic stiffness [86] and concentric remodeling [87], whereas IL-1-β can induce diastolic dysfunction by altering calcium handling, decreasing the expression of SERCA (sarcoplasmic reticulum calcium ATPase), and phospholamban (PLB) and, therefore, calcium recaptured [56].…”

Section: The Heart As a Target Of Systemic Inflammationmentioning

confidence: 99%

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

et al. 2020

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Purpose of Review In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. Recent Findings Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. Summary In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.

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Mechanisms of mitochondrial DNA escape and its relationship with different metabolic diseases

Cited by 93 publications

References 115 publications

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

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