Cardiac Involvement in Mitochondrial Disorders

Popoiu, Tudor-Alexandru; Dudek, Jan; Maack, Christoph; Bertero, Edoardo

doi:10.1007/s11897-023-00592-3

Cited by 7 publications

(4 citation statements)

References 130 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The heart has a high-energy requirement, and in cardiac myocytes, mitochondria occupy approximately one third of the cell volume [58]. Cardiac damage in the non-diabetic XM is in keeping with cardiac damage and cardiomyopathy in humans with mitochondrial disorders [59].…”

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to ‘Mismatched’ Mitochondrial DNA

Januszewski,

Blake,

Zhang

et al. 2024

Antioxidants

View full text Add to dashboard Cite

Associations between chronic diabetes complications and mitochondrial dysfunction represent a subject of major importance, given the diabetes pandemic and high personal and socioeconomic costs of diabetes and its complications. Modelling diabetes complications in inbred laboratory animals is challenging due to incomplete recapitulation of human features, but offer mechanistic insights and preclinical testing. As mitochondrial-based oxidative stress is implicated in human diabetic complications, herein we evaluate diabetes in a unique mouse model that harbors a mitochondrial DNA from a divergent mouse species (the ‘xenomitochondrial mouse’), which has mild mitochondrial dysfunction and increased oxidative stress. We use the streptozotocin-induced diabetes model with insulin supplementation, with 20-weeks diabetes. We compare C57BL/6 mice and the ‘xenomitochondrial’ mouse, with measures of heart and kidney function, histology, and skin oxidative stress markers. Compared to C57BL/6 mice, the xenomitochondrial mouse has increased diabetic heart and kidney damage, with cardiac dysfunction, and increased cardiac and renal fibrosis. Our results show that mitochondrial oxidative stress consequent to divergent mtDNA can worsen diabetes complications. This has implications for novel therapeutics to counter diabetes complications, and for genetic studies of risk, as mtDNA genotypes may contribute to clinical outcomes.

show abstract

Section: Discussionmentioning

confidence: 84%

“…Study strengths include the use of a novel mouse model with mitochondrial dysfunction, which as in human mitochondrial disease has mild cardiac dysfunction even in the absence of diabetes [59,62]. In addition, we used this model to test if diabetes tissue damage is aggravated by mitochondrial dysfunction.…”

Section: Study Strengths and Limitationsmentioning

confidence: 99%

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to ‘Mismatched’ Mitochondrial DNA

Januszewski,

Blake,

Zhang

et al. 2024

Antioxidants

View full text Add to dashboard Cite

show abstract

“…At the cardiac level, histological analysis of polg2 ia304/ia304 mutants detected decreased atrium and ventricle dimensions compared to wt, reflecting a reduced development of heart muscle and altered trabecular network, which might recall the cardiomyopathies often reported in mitochondrial disorders [ 34 ]. This feature is also congruent with a reduced development of other high-energy demanding tissues in polg2 mutants, as oxygen supply is expected to be compromised by systemic cardiovascular insufficiency.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment

Brañas Casas,

Zuppardo,

Risato

et al. 2024

Cell Death Dis

View full text Add to dashboard Cite

The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.

show abstract

“…Yet, local starvation of substrates may account for spatial adjustment of bioenergetics. Under physiologic conditions, fatty acid oxidation generates 60%–90% of ATP whilst oxidation of carbohydrates, and to a lesser degree ketones and amino acids provide the remaining 10%–40% ( Bertero and Maack, 2018 ; Popoiu et al, 2023 ). The Randle cycle ( Randle et al, 1963 ; Hue and Taegtmeyer, 2009 ) may thus become metabolically relevant when fatty acid oxidation outpaces intracellular transport mechanisms.…”

Section: Potential Modes Of Spatial Oxphos Adjustmentmentioning

confidence: 99%

Spatial adjustment of bioenergetics, a possible determinant of contractile adaptation and development of contractile failure

Szibor,

Mühlon,

Doenst

et al. 2023

Front. Mol. Med

View full text Add to dashboard Cite

Cardiomyocytes depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy metabolism, which is facilitated by the mitochondrial electron transfer system (ETS). In a series of thermogenic redox reactions, electrons are shuttled through the ETS to oxygen as the final electron acceptor. This electron transfer is coupled to proton translocation across the inner mitochondrial membrane, which itself is the main driving force for ATP production. Oxygen availability is thus a prerequisite for ATP production and consequently contractility. Notably, cardiomyocytes are exceptionally large cells and densely packed with contractile structures, which constrains intracellular oxygen distribution. Moreover, oxygen must pass through layers of actively respiring mitochondria to reach the ones located in the innermost contractile compartment. Indeed, uneven oxygen distribution was observed in cardiomyocytes, suggesting that local ATP supply may also vary according to oxygen availability. Here, we discuss how spatial adjustment of bioenergetics to intracellular oxygen fluctuations may underlie cardiac contractile adaptation and how this adaptation may pose a risk for the development of contractile failure.

show abstract

Cardiac Involvement in Mitochondrial Disorders

Cited by 7 publications

References 130 publications

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to ‘Mismatched’ Mitochondrial DNA

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to ‘Mismatched’ Mitochondrial DNA

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment

Spatial adjustment of bioenergetics, a possible determinant of contractile adaptation and development of contractile failure

Contact Info

Product

Resources

About