Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Q: What are the key findings of this study?

The MT-RNR2 m.2336T>C mutation decreased 16S rRNA levels by 55% (p<0.01), reduced the ATP/ADP ratio to 47% of control (p<0.01), and elevated intracellular Ca2+ from 131 to 213 nmol/L (p<0.05).

Q: What is the clinical evidence from this study?

Population: Maternally inherited hypertrophic cardiomyopathy (HCM) with MT-RNR2 m.2336T>C mutation (n=4). Intervention: MT-RNR2 m.2336T>C mutation vs. Control iPSC-derived cardiomyocytes without the m.2336T>C mutation (from the proband's unaffected son and two genetically unrelated healthy individuals). Primary outcome: Intracellular Ca2+ concentration ([Ca2+]i) in iPSC-derived cardiomyocytes (p=<0.05).

Q: What does this research mean for the field?

The mitochondrial MT-RNR2 m.2336T>C mutation causes mitochondrial dysfunction, reduced ATP/ADP ratios, and elevated intracellular calcium levels, driving hypertrophic cardiomyopathy pathogenesis in human cardiomyocytes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Shishi Li; Huaye Pan; Chao Tan; Yaping Sun; Yanrui Song; Xuan Zhang; Wei Yang; Xuexiang Wang; Dan Li; Yu Dai; Qiang Ma; Chenming Xu; Xu‐Fen Zhu; Lijun Kang; Yong Fu; Xuejun Xu; Jing Shu; Naiming Zhou; Han Feng; Dajiang Qin; Wendong Huang; Zhong Liu; Qingfeng Yan

doi:10.1016/j.stemcr.2018.01.013

Key result

Mitochondrial m.2336T>C mutation elevates cardiomyocyte intracellular calcium ~63% while disrupting cellular bioenergetics.

P<0.05
n=4

Figures

Why the study?

Does the mitochondrial MT-RNR2 m.2336T>C mutation cause mitochondrial dysfunction, abnormal calcium handling, and hypertrophic cardiomyopathy electrophysiological phenotypes in patient iPSC-derived cardiomyocytes?

Key Points

Investigate the molecular mechanisms linking the mitochondrial 16S rRNA gene (MT-RNR2) m.2336T>C mutation to hypertrophic cardiomyopathy using patient-derived cardiomyocytes.
Reprogrammed urine cells from an HCM patient carrying the m.2336T>C mutation and healthy controls into induced pluripotent stem cells (iPSCs).
Differentiated iPSCs into mature cardiomyocytes (iPSC-CMs) using a monolayer myocardial differentiation protocol, maintaining spontaneously beating cells for over 4 months.
Assessed cardiomyocyte size, mitochondrial ultrastructure by transmission electron microscopy, mtDNA copy number, and electrophysiological properties.
HCM-iPSC-CMs displayed disordered beating and were approximately 27% larger than control cells, with significantly higher nuclear NFATC4 positivity (43.1% vs 26.1%, p < 0.05).
MtDNA copy number increased by 71.2% in HCM-iPSC-CMs (1,236 ± 107 vs 722 ± 51, p < 0.05), accompanied by round-shaped mitochondria with underdeveloped cristae.
The m.2336T>C mutation decreased 16S rRNA stability, reduced mitochondrial proteins, lowered the ATP/ADP ratio and membrane potential, and elevated intracellular calcium levels.

Structured PICO

Does the mitochondrial MT-RNR2 m.2336T>C mutation cause mitochondrial dysfunction, abnormal calcium handling, and hypertrophic cardiomyopathy electrophysiological phenotypes in patient iPSC-derived cardiomyocytes?

P

Population

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from 1 proband with maternally inherited hypertrophic cardiomyopathy carrying the MT-RNR2 m.2336T>C mutation and 3 healthy controls in China.

E

Exposure

MT-RNR2 m.2336T>C mitochondrial 16S rRNA gene mutation in patient-derived HCM-iPSC-CMs

C

Comparator

Control iPSC-derived cardiomyocytes (Con-iPSC-CMs) from healthy individuals without the m.2336T>C mutation

O

Outcome

Cellular hypertrophy, mitochondrial morphology and function (16S rRNA stability, mitochondrial protein levels, mitochondrial membrane potential, ATP/ADP ratio), intracellular calcium homeostasis ([Ca2+]i and L-type Ca2+ current), and electrophysiological properties (action potential duration and delayed afterdepolarizations)surrogate

Main Result

Absolute Event Rate: 213% vs 131%

p-value: p=<0.05

This patient-derived iPSC-CM model demonstrates that the mitochondrial MT-RNR2 m.2336T>C mutation destabilizes 16S rRNA, impairs mitochondrial bioenergetics, and disrupts intracellular calcium homeostasis to drive cellular hypertrophy and arrhythmogenesis in maternally inherited HCM.

Limitations

Integration of retroviral vectors into the host genome during Yamanaka factor-based reprogramming potentially causes immunogenicity and tumorigenesis, hindering clinical application.
Human iPSC-derived cardiomyocytes exhibit high phenotypic immaturity and variability compared with adult cardiomyocytes.
Action potentials were recorded from spontaneously beating cells rather than cells stimulated at a fixed frequency, which might bias action potential duration values due to different baseline beating frequencies.
Integration of retroviral vectors into the host genome potentially causes immunogenicity and tumorigenesis and hinders clinical application
Human iPSC-derived cardiomyocytes exhibit high phenotypic immaturity and variability compared with adult cardiomyocytes
Action potentials were recorded from spontaneously beating cells rather than cells stimulated at a fixed frequency, potentially biasing APD values

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Supports MT-RNR2 mutation modeling in iPSC-CMs for HCM mechanisms; leaves open clinical translation or therapeutic targeting.

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young individuals. A potential role of mtDNA mutations in HCM is known. However, the underlying molecular mechanisms linking mtDNA mutations to HCM remain poorly understood due to lack of cell and animal models. Here, we generated induced pluripotent stem cell-derived cardiomyocytes (HCM-iPSC-CMs) from human patients in a maternally inherited HCM family who carry the m.2336T>C mutation in the mitochondrial 16S rRNA gene ( MT-RNR2 ). The results showed that the m.2336T>C mutation resulted in mitochondrial dysfunctions and ultrastructure defects by decreasing the stability of 16S rRNA , which led to reduced levels of mitochondrial proteins. The ATP/ADP ratio and mitochondrial membrane potential were also reduced, thereby elevating the intracellular Ca 2+ concentration, which was associated with numerous HCM-specific electrophysiological abnormalities. Our findings therefore provide an innovative insight into the pathogenesis of maternally inherited HCM.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Li et al. (2018) studied Maternally inherited hypertrophic cardiomyopathy (HCM) with MT-RNR2 m.2336T>C mutation (n=4). MT-RNR2 m.2336T>C mutation vs. Control iPSC-derived cardiomyocytes without the m.2336T>C mutation (from the proband's unaffected son and two genetically unrelated healthy individuals) was evaluated on Intracellular Ca2+ concentration ([Ca2+]i) in iPSC-derived cardiomyocytes (p=<0.05). The MT-RNR2 m.2336T>C mutation decreased 16S rRNA levels by 55% (p<0.01), reduced the ATP/ADP ratio to 47% of control (p<0.01), and elevated intracellular Ca2+ from 131 to 213 nmol/L (p<0.05).

synapsesocial.com/papers/6a7a26325968508e56f3b00c https://doi.org/10.1016/j.stemcr.2018.01.013

View Full Paper

Ask AI

Bookmark

Share

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading