Mitochondria: Dynamic Organelles in Disease, Aging, and Development

Chan, David C.

doi:10.1016/j.cell.2006.06.010

Cited by 1,773 publications

(1,468 citation statements)

References 90 publications

Supporting

Mentioning

1,398

Contrasting

Unclassified

Order By: Relevance

“…We scored individual mitochondrion according to the severity of its phenotype blindly in normal and HGPS samples (Materials and methods). As vulnerable targets of ROS, mitochondria can display some abnormalities under normal physiological conditions (Chan, 2006). These defects are similar to what we categorized here as ‘minor defects’, which showed similar proportions in both normal and HGPS samples.…”

Section: Resultsmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

View full text Add to dashboard Cite

SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

show abstract

Section: Resultsmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Together, these results suggest that mitochondrial function is compromised under hemodynamic stress conditions and exacerbated by the deletion of cardiac Gab1 that could trigger caspase activation and consequent apoptosis of cardiomyocytes and heart failure. 34,35 Mice with cardiac Gab1 deficiency developed spontaneous DCM and heart failure by 3-6 months of age. Mitochondrial dysfunction and mitochondria oxidative stress have linked to age-related heart diseases.…”

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

View full text Add to dashboard Cite

A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

show abstract

“…In the following section we will review the fission/fusion machinery focusing on the proteins that have been shown to be involved in mammalian cell death (Table 1). For a more detailed discussion of mitochondrial fission/fusion machinery see review [34][35][36][37][38][39][40].…”

Section: Overview Of Mitochondrial Membrane Dynamics Machinementioning

confidence: 99%

“…As with mitochondrial fission, the fusion machinery also plays an essential role in development and survival [35,77,78]. Fusion is thought to protect mitochondrial function by allowing rapid mixing of membranes, mitochondrial DNA and soluble contents that may be damaged by localized deficits of substrates as a result of cellular stress [35].…”

Section: Mitochondrial Fusion and Cell Deathmentioning

confidence: 99%

“…Fusion is thought to protect mitochondrial function by allowing rapid mixing of membranes, mitochondrial DNA and soluble contents that may be damaged by localized deficits of substrates as a result of cellular stress [35]. Recently, several studies indicated that during cell death mitochondrial fusion is inhibited and activation of the fusion machinery could slow down the rate of cell death [29,69,79].…”

Section: Mitochondrial Fusion and Cell Deathmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial dynamics in the regulation of neuronal cell death

2007

View full text Add to dashboard Cite

Mitochondria undergo continuous fission and fusion events in physiological situations. Fragmentation of mitochondria during cell death has been shown to play a key role in cell death progression, including release of the mitochondrial apoptotic proteins. Ultrastructural changes in mitochondria, such as cristae remodeling, is also involved in cell death initiation. Here, we emphasize the important role of mitochondrial fission/fusion machinery in neuronal cell death. Unlike many other cell types such as immortalized cell lines, neurons are distinct morphologically and functionally. We will discuss how this uniqueness presents special challenges in the cellular response to neurotoxic stresses, and how this affects the mitochondrial dynamics in the regulation of cell death in neurons.

show abstract

Mitochondria: Dynamic Organelles in Disease, Aging, and Development

Cited by 1,773 publications

References 90 publications

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Mitochondrial dynamics in the regulation of neuronal cell death

Contact Info

Product

Resources

About