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Disorders of Mitochondrial Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 24858

Special Issue Editor

Special Issue Information

Dear Colleagues,

Disorders of mitochondrial metabolism are a phenotypically and genetically diverse group of diseases which can affected any organ or tissue of the body, although organs with high energy demands such as the brain and muscle tissue are generally most susceptible. One of the major causes of impaired mitochondrial metabolism are mitochondrial respiratory chain (MRC) disorders which have an estimated incidence of 1 in 5000. MRC dysfunction can present at any age and result from mutations in either mitochondrial or nuclear DNA and therefore both matrilineal and Mendelian inheritance patterns are exhibited by families with these conditions. In addition to primary genetic causes, MRC dysfunction may also result from the secondary consequence of disease pathophysiology as well as from `off target` drug toxicity.

The purpose of this Special Issue will be to present a selection of studies and reviews that outline the causes and consequences of primary and secondary MRC dysfunction, including putative mechanisms of mitochondrial impairment, appropriate diagnostic biomarkers of disease pathophysiology and candidate therapies.

Dr. Iain Hargreaves
Guest Editor

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Published Papers (5 papers)

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Research

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12 pages, 3338 KiB  
Article
Opa1 Deficiency Promotes Development of Retinal Vascular Lesions in Diabetic Retinopathy
by Dongjoon Kim, Marcela Votruba and Sayon Roy
Int. J. Mol. Sci. 2021, 22(11), 5928; https://doi.org/10.3390/ijms22115928 - 31 May 2021
Cited by 8 | Viewed by 2343
Abstract
This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− [...] Read more.
This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− mice were used in this study. 16 weeks after diabetes onset, retinas were assessed for Opa1 and Bax levels by Western blot analysis, and retinal networks were examined for acellular capillaries (AC) and pericyte loss (PL). Apoptotic cells were detected in retinal capillaries using TUNEL assay, and caspase-3 activity was assessed using fluorometric analysis. Opa1 expression was significantly downregulated in retinas of diabetic and Opa1+/− mice compared with those of WT mice. Inducing diabetes further decreased Opa1 expression in retinas of Opa1+/− mice. Increased cytochrome c release concomitant with increased level of pro-apoptotic Bax and elevated caspase-3 activity were observed in retinas of diabetic and Opa1+/− mice; the number of TUNEL-positive cells and AC/PL was also significantly increased. An additional decrease in the Opa1 level in retinas of diabetic Opa1+/− mice exacerbated the development of apoptotic cells and AC/PL compared with those of diabetic mice. Diabetes-induced Opa1 downregulation contributes, at least in part, to the development of retinal vascular lesions characteristic of DR. Full article
(This article belongs to the Special Issue Disorders of Mitochondrial Metabolism)
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Review

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13 pages, 695 KiB  
Review
The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders
by Nadia Turton, Neve Cufflin, Mollie Dewsbury, Olivia Fitzpatrick, Rahida Islam, Lowidka Linares Watler, Cara McPartland, Sophie Whitelaw, Caitlin Connor, Charlotte Morris, Jason Fang, Ollie Gartland, Liv Holt and Iain P. Hargreaves
Int. J. Mol. Sci. 2022, 23(13), 7487; https://doi.org/10.3390/ijms23137487 - 5 Jul 2022
Cited by 3 | Viewed by 6504
Abstract
Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and [...] Read more.
Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and amino acid levels, as well as urine organic acids. Recently, hormone-like cytokines, such as fibroblast growth factor-21 (FGF-21), have also been used as a means of assessing evidence of MRC dysfunction, although work is still required to confirm their diagnostic utility and reliability. The assessment of evidence of oxidative stress may also be an important parameter to consider in the diagnosis of MRC function in view of its association with mitochondrial dysfunction. At present, due to the lack of reliable biomarkers available for assessing evidence of MRC dysfunction, the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ is considered the ‘Gold Standard’ biochemical method to provide evidence of MRC dysfunction. The purpose of this review is to outline a number of biochemical methods that may provide diagnostic evidence of MRC dysfunction in patients. Full article
(This article belongs to the Special Issue Disorders of Mitochondrial Metabolism)
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33 pages, 1838 KiB  
Review
Mitochondrial Pathophysiology on Chronic Kidney Disease
by Patrícia C. Braga, Marco G. Alves, Anabela S. Rodrigues and Pedro F. Oliveira
Int. J. Mol. Sci. 2022, 23(3), 1776; https://doi.org/10.3390/ijms23031776 - 4 Feb 2022
Cited by 30 | Viewed by 4925
Abstract
In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve [...] Read more.
In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression. Full article
(This article belongs to the Special Issue Disorders of Mitochondrial Metabolism)
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35 pages, 3884 KiB  
Review
Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases
by Lauren Elizabeth Millichap, Elisabetta Damiani, Luca Tiano and Iain P. Hargreaves
Int. J. Mol. Sci. 2021, 22(21), 11444; https://doi.org/10.3390/ijms222111444 - 23 Oct 2021
Cited by 21 | Viewed by 7286
Abstract
Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species [...] Read more.
Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders. Full article
(This article belongs to the Special Issue Disorders of Mitochondrial Metabolism)
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20 pages, 1320 KiB  
Review
Cellular Models for Primary CoQ Deficiency Pathogenesis Study
by Carlos Santos-Ocaña, María V. Cascajo, María Alcázar-Fabra, Carmine Staiano, Guillermo López-Lluch, Gloria Brea-Calvo and Plácido Navas
Int. J. Mol. Sci. 2021, 22(19), 10211; https://doi.org/10.3390/ijms221910211 - 22 Sep 2021
Cited by 7 | Viewed by 2815
Abstract
Primary coenzyme Q10 (CoQ) deficiency includes a heterogeneous group of mitochondrial diseases characterized by low mitochondrial levels of CoQ due to decreased endogenous biosynthesis rate. These diseases respond to CoQ treatment mainly at the early stages of the disease. The advances in [...] Read more.
Primary coenzyme Q10 (CoQ) deficiency includes a heterogeneous group of mitochondrial diseases characterized by low mitochondrial levels of CoQ due to decreased endogenous biosynthesis rate. These diseases respond to CoQ treatment mainly at the early stages of the disease. The advances in the next generation sequencing (NGS) as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have increased the discoveries of mutations in either gene already described to participate in CoQ biosynthesis or new genes also involved in this pathway. However, these technologies usually provide many mutations in genes whose pathogenic effect must be validated. To functionally validate the impact of gene variations in the disease’s onset and progression, different cell models are commonly used. We review here the use of yeast strains for functional complementation of human genes, dermal skin fibroblasts from patients as an excellent tool to demonstrate the biochemical and genetic mechanisms of these diseases and the development of human-induced pluripotent stem cells (hiPSCs) and iPSC-derived organoids for the study of the pathogenesis and treatment approaches. Full article
(This article belongs to the Special Issue Disorders of Mitochondrial Metabolism)
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