Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Abstract

SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

“…Cardiac dysfunction was associated with nuclear enrichment of Cap and collar C (CncC) [the orthologue of mammalian nuclear erythroid 2-related factor 2 (Nrf2)], suggesting cellular redox imbalance in flies with Lamin C mutations. Upregulating autophagy by Atg1 overexpression in this model attenuated cytoplasmic Lamin C accumulation, improved nuclear morphology, promoted myofibrillar organization, and ameliorated cardiac dysfunction [92]. Overall, this study demonstrated that upregulating autophagy improved the clearance capacity of cardiac cells to an extent that restored cardiac function.…”

“…Of particular relevance to this review, a common manifestation of Lamin A/C mutations and the subsequent accumulation of progerin caused cardiac dysfunction manifested by atrial arrhythmia and hypertrophic cardiomyopathy [90,91]. Evidence supporting this link is provided by a fly model of cardiolaminopathy exhibiting repressed autophagy, accumulation of cytoplasmic Lamin C aggregates, impaired cardiac function, severe myofibrillar degeneration, nuclear morphological defects, and evidence of oxidative stress [92]. Cardiac dysfunction was associated with nuclear enrichment of Cap and collar C (CncC) [the orthologue of mammalian nuclear erythroid 2-related factor 2 (Nrf2)], suggesting cellular redox imbalance in flies with Lamin C mutations.…”

The Dark Side of Nrf2 in the Heart

“…Collectively, our findings suggest that autophagy impairment switches on Nrf2-mediated cardiac pathological remodeling and dysfunction. Interestingly, Bhide et al (2018) documented that in a Drosophila model of laminopathy, laminopathy-associated age-dependent cardiac dysfunction, could be rescued by knockdown of Nrf2, or enhancement of autophagy in the heart. These findings suggest that age-dependent autophagy deficiency may turn on Nrf2-mediated cardiac dysfunction in the Drosophila model of laminopathy.…”

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

“…RNAi-mediated knockdown of PINK1 remarkably rescued CHCHD10 S59L -induced mitochondrial morphologic and functional defects in HeLa cells ( (45,46). However, strong mitochondrial abnormalities in PRKN-deficient HeLa cells indicate the presence of parkin-independent toxic mechanisms.…”