Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure

2015 ◽  
Vol 309 (3) ◽  
pp. H434-H449 ◽  
Author(s):  
Knut H. Lauritzen ◽  
Liv Kleppa ◽  
Jan Magnus Aronsen ◽  
Lars Eide ◽  
Harald Carlsen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Fission ◽  
Clinical Manifestations ◽  
Premature Death ◽  
Specific Expression ◽  
Mitochondrial Homeostasis ◽  
Transport Chain ◽  
Mtdna Replication ◽  
Dynamics And Function ◽  
And Function

Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ∼2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease.

scholarly journals Mitochondrial fission is required for proper nucleoid distribution within mitochondrial networks

2021 ◽  
Author(s):  
Hema Saranya Ilamathi ◽  
Mathieu Ouellet ◽  
Rasha Sabouny ◽  
Justine Desrochers-Goyette ◽  
Matthew A Lines ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Network Structure ◽  
Mitochondrial Fission ◽  
Healthy Population ◽  
Primary Cells ◽  
Mitochondrial Homeostasis ◽  
Mtdna Replication ◽  
Mitochondrial Networks ◽  
Regular Spacing

Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.

scholarly journals DRP1 regulates endoplasmic reticulum sheets to control mitochondrial DNA replication and segregation

2021 ◽  
Author(s):  
Hema Saranya Ilamathi ◽  
Sara Benhammouda ◽  
Justine Desrochers-Goyette ◽  
Matthew A Lines ◽  
Marc Germain
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitochondrial Dna ◽  
Protein Complexes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Diseases ◽  
Contact Sites ◽  
Transport Chain ◽  
Essential Components ◽  
Mtdna Replication

Mitochondria are multi-faceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) codes for several essential components of the electron transport chain, and mtDNA maintenance defects lead to mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is regulated by mitochondrial dynamics. Specifically, mitochondrial fusion is essential for mtDNA maintenance. In contrast, while loss of mitochondrial fission causes the aggregation of nucleoids (mtDNA-protein complexes), its role in nucleoid distribution remains unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering ER sheets, the ER structure associated with protein synthesis. Specifically, DRP1 loss or mutation leads to altered ER sheets that physically interact with mitobulbs, mitochondrial structures containing aggregated nucleoids. Importantly, nucleoid distribution and mtDNA replication were rescued by expressing the ER sheet protein CLIMP63. Thus, our work identifies a novel mechanism by which DRP1 regulates mtDNA replication and distribution.

scholarly journals Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure

2020 ◽  
Vol 9 (11) ◽  
pp. 3582
Author(s):  
Antoine H. Chaanine ◽  
Thierry H. LeJemtel ◽  
Patrice Delafontaine
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Ion Homeostasis ◽  
Systolic Heart Failure ◽  
Redox Balance ◽  
High Energy ◽  
Mitochondrial Morphology ◽  
Metabolic Remodeling ◽  
Dynamics And Function ◽  
And Function

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure.

scholarly journals The right-sided heart failure

2019 ◽  
Vol 29 (2) ◽  
pp. 135-147
Author(s):  
A. G. Chuchalin
Keyword(s):  
Heart Failure ◽  
Clinical Manifestations ◽  
Clinical Syndrome ◽  
Lv Function ◽  
Right Heart ◽  
Heart Abnormalities ◽  
Lv Volume ◽  
The Right ◽  
And Function ◽  
Heart Physiology

The right-sided heart failure (RSHF) is a complex clinical syndrome including different pathogenic mechanisms and processes resulted from the right ventricle (RV) dysfunction and manifested with signs of heart failure (HF). Recently, there is a growing scientific interest in the right-sided acute and chronic heart abnormalities; this is due to growing knowledge in this field and development of novel diagnostic, therapeutic and pharmacological approaches to treatment of pulmonary hypertension that is a common cause of RSHF. Cardiac embryogenesis, anatomic particularities, difference and interdependence of RV and the left ventricle (LV) are described in the article in order to improve the knowledge on structure and function of both the right heart and the left heart. Discussion on pathophysiology, causes and clinical manifestations of acute RSHF (aRSHF) and chronic RSHF (cRSHF) should consider the right heart physiology. Pharmacological treatment should be targeted to ventricle pre-load, myocardial contractility and RV post-load, correction of pulmonary circulation and LV volume resulting in post-load reduction and improvement in the LV function. Patients with biventricular dysfunction should be treated according to current clinical guidelines on therapy of chronic HF. Vasoactive agents and diuretics have an important role for the treatment of RSHF as this is the basic therapy of pulmonary congestion both in aRSHF and cRSHF. Step-by-step therapeutic algorithm is given in the article.

scholarly journals A new automated tool to quantify nucleoid distribution within mitochondrial networks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hema Saranya Ilamathi ◽  
Mathieu Ouellet ◽  
Rasha Sabouny ◽  
Justine Desrochers-Goyette ◽  
Matthew A. Lines ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Fission ◽  
Healthy Population ◽  
Primary Cells ◽  
Mitochondrial Homeostasis ◽  
Mtdna Replication ◽  
Mitochondrial Networks ◽  
Automated Tool ◽  
Regular Spacing

AbstractMitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.

scholarly journals Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Chowdhury S. Abdullah ◽  
Richa Aishwarya ◽  
Shafiul Alam ◽  
Mahboob Morshed ◽  
Naznin Sultana Remex ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Illicit Drug ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Element Binding Protein ◽  
Dynamics And Function ◽  
And Function

AbstractMethamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.

scholarly journals FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

2016 ◽  
Vol 311 (6) ◽  
pp. H1540-H1559 ◽  
Author(s):  
Antoine H. Chaanine ◽  
Erik Kohlbrenner ◽  
Scott I. Gamb ◽  
Adam J. Guenzel ◽  
Katherine Klaus ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dynamics ◽  
Left Ventricular ◽  
Attractive Potential ◽  
Mitochondrial Morphology ◽  
Cardiac Stress ◽  
Virus Serotype ◽  
Dynamics And Function ◽  
And Function

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .

scholarly journals Evidence of Mitochondrial Dysfunction in Bacterial Chondronecrosis With Osteomyelitis–Affected Broilers

2021 ◽  
Vol 8 ◽  
Author(s):  
Alison Ferver ◽  
Elizabeth Greene ◽  
Robert Wideman ◽  
Sami Dridi
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Bacterial Infections ◽  
Mitochondrial Fission ◽  
Cellular Respiration ◽  
Mrna Levels ◽  
Mechanistic Investigation ◽  
Causative Agents ◽  
Dynamics And Function ◽  
And Function

A leading cause of lameness in modern broilers is bacterial chondronecrosis with osteomyelitis (BCO). While it is known that the components of BCO are bacterial infection, necrosis, and inflammation, the mechanism behind BCO etiology is not yet fully understood. In numerous species, including chicken, mitochondrial dysfunction has been shown to have a role in the pathogenicity of numerous diseases. The mitochondria is a known target for intracellular bacterial infections, similar to that of common causative agents in BCO, as well as a known regulator of cellular metabolism, stress response, and certain types of cell death. This study aimed to determine the expression profile of genes involved in mitochondrial biogenesis, dynamics, and function. RNA was isolated form the tibias from BCO-affected and healthy broilers and used to measure target gene expression via real-time qPCR. Mitochondrial biogenesis factors PGC-1α and PGC-1β were both significantly upregulated in BCO along with mitochondrial fission factors OMA1, MTFR1, MTFP1, and MFF1 as well as cellular respiration-related genes FOXO3, FOXO4, and av-UCP. Conversely, genes involved in mitochondrial function, ANT, COXIV, and COX5A showed decreased mRNA levels in BCO-affected tibia. This study is the first to provide evidence of potential mitochondrial dysfunction in BCO bone and warrants further mechanistic investigation into how this dysfunction contributes to BCO etiology.

scholarly journals Hexestrol Deteriorates Oocyte Quality via Perturbation of Mitochondrial Dynamics and Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Dong Niu ◽  
Kun-Lin Chen ◽  
Yi Wang ◽  
Xiao-Qing Li ◽  
Lu Liu ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Oocyte Maturation ◽  
Ovarian Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Oocyte Quality ◽  
Early Embryo ◽  
Mitochondrial Distribution ◽  
Dynamics And Function ◽  
And Function

Hexestrol (HES) is a synthetic non-steroidal estrogen that was widely used illegally to boost the growth rate in livestock production and aquaculture. HES can also be transferred to humans from treated animals and the environment. HES has been shown to have an adverse effect on ovarian function and oogenesis, but the potential mechanism has not been clearly defined. To understand the potential mechanisms regarding how HES affect female ovarian function, we assessed oocyte quality by examining the critical events during oocyte maturation. We found that HES has an adverse effect on oocyte quality, indicated by the decreased capacity of oocyte maturation and early embryo development competency. Specifically, HES-exposed oocytes exhibited aberrant microtubule nucleation and spindle assembly, resulting in meiotic arrest. In addition, HES exposure disrupted mitochondrial distribution and the balance of mitochondrial fission and fusion, leading to aberrant mitochondrial membrane potential and accumulation of reactive oxygen species. Lastly, we found that HES exposure can increase cytosolic Ca2+ levels and induce DNA damage and early apoptosis. In summary, these results demonstrate that mitochondrial dysfunction and perturbation of normal mitochondrial fission and fusion dynamics could be major causes of reduced oocyte quality after HES exposure.

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