Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases

Catalán-García, Marc; García-García, Francesc Josep; Moreno-Lozano, Pedro; Alcarraz-Vizán, Gema; Tort‐Merino, Adrià; Milisenda, José César; Cantó-Santos, Judith; Barcos, Tamara; Cardellach, Francesc; Lladó, Albert; Novials, Anna; Garrabou, Glòria; Grau-Junyent, Josep María

doi:10.3390/jcm9051446

Cited by 8 publications

(3 citation statements)

References 62 publications

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“…The 31 P-magnetic resonance spectroscopy assessments revealed that the muscle of sIBM patients has a low ability to synthesize ATP during resting, further supporting the notion of impaired mitochondrial respiration in sIBM ( Lodi et al, 1998 ). A recent study also reported diminished mitochondrial enzymatic activities in cultured sIBM myofibers under low glucose availability, indicating compromised metabolic flexibility ( Catalán-García et al, 2020 ). Consequently, this low mitochondrial activity might significantly impact the overall function of skeletal muscle, causing weakness in contraction strength and endurance ( Gonzalez-Chapa et al, 2023 ).…”

Section: Presence Of Abnormal Mitochondria In Sibmmentioning

confidence: 98%

Mitochondrial defects in sporadic inclusion body myositis—causes and consequences

Iu,

So,

Chan

2024

Front. Cell Dev. Biol.

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Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation of the immune system is widely believed as the primary cause of IIM, it is debated whether non-immune tissue dysfunction might contribute to the disease’s onset as patients with sIBM are refractory to conventional immunosuppressant treatment. Moreover, the findings that mitochondrial dysfunction can elicit non-apoptotic programmed cell death and the subsequent immune response further support this hypothesis. Notably, abnormal mitochondrial structure and activities are more prominent in the muscle of sIBM than in other types of IIM, suggesting the presence of defective mitochondria might represent an overlooked contributor to the disease onset. The large-scale mitochondrial DNA deletion, aberrant protein aggregation, and slowed organelle turnover have provided mechanistic insights into the genesis of impaired mitochondria in sIBM. This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed.

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Section: Presence Of Abnormal Mitochondria In Sibmmentioning

confidence: 98%

Mitochondrial defects in sporadic inclusion body myositis—causes and consequences

Iu,

So,

Chan

2024

Front. Cell Dev. Biol.

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“…International Publisher proteasome impairment, accumulation of abnormal protein aggregates and mitochondrial dysfunction [6,7]. Of these, mitochondrial dysfunction is a recurring theme, particularly in common diseases [8][9][10]; such as Parkinson's (PD) and Alzheimer's (AD) diseases that together affect ~10% of population, and diabetic retinopathy, the most common form of blindness in working aged people [11,12]. How a mitochondrial defect leads to tissue destruction and subsequent loss of functional neurons remains, however, unclear.…”

Section: Ivyspringmentioning

confidence: 99%

Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation

Liang,

Chen,

Kianian

et al. 2024

Int. J. Biol. Sci.

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Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD + /NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.

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“…Although genetic targets have been identified, mitochondrial disease presents interindividual heterogeneity and can be challenging to diagnose [2]. Mitochondrial disease has also been shown to present with comorbidities, such as diabetes and Parkinson's disease [3]. This is due to the high abundance of mitochondria in virtually every cell of the body.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and health care costs of mitochondrial disease in Ontario, Canada: A population-based cohort study

et al. 2022

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Background Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though multi-linked health administrative data resources present a unique opportunity to establish robust population-based estimates in a single-payer health system. This study used administrative data for the Ontario, Canada population between April 1988 and March 2019 to measure mitochondrial disease prevalence and describe patient characteristics and health care costs. Results 3069 unique individuals were hospitalized with mitochondrial disease in Ontario and eligible for the study cohort, representing a period prevalence of 2.51 per 10,000 or 1 in 3989. First hospitalization was most common between ages 0–9 or 50–69. The mitochondrial disease population experiences a high need for health care and incurred high costs (mean = CAD$24,023 in 12 months before first hospitalization) within the single-payer Ontario health care system. Conclusions This study provides needed insight into mitochondrial disease in Canada, and demonstrates the high health burden on patients. The methodology used can be adapted across jurisdictions with similar routine collection of health data, such as in other Canadian provinces. Future work should seek to validate this approach via record linkage of existing disease cohorts in Ontario, and identify specific comorbidities with mitochondrial disease that may contribute to high health resource utilization.

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Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases

Cited by 8 publications

References 62 publications

Mitochondrial defects in sporadic inclusion body myositis—causes and consequences

Mitochondrial defects in sporadic inclusion body myositis—causes and consequences

Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation

Prevalence and health care costs of mitochondrial disease in Ontario, Canada: A population-based cohort study

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