[citation report] Titration of mitochondrial fusion rescues <i>Mff</i>-deficient cardiomyopathy

Cited by 137 publications

(122 citation statements)

References 32 publications

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“…Previous reports suggested that mitochondrial autophagy is stimulated rather than inhibited when Drp1 or Miff, a major receptor for Drp1, is downregulated 26, 27 . Our study used Mito-Keima, EM, and evaluation of mitochondrial content, while the other study used mitochondrial accumulation of p62 and LC3-II, aggregation of Parkin, and co-localization of mitochondrial proteins and lysosomes as indicators of mitophagy 26 .…”

Section: Discussionmentioning

confidence: 95%

“…It has been shown recently that cardiac and mitochondrial dysfunction caused by downregulation of Miff can be rescued by concomitant downregulation of Mfn1 27 , suggesting that balancing mitochondrial fusion and fission is critical for the maintenance of mitochondrial function in the heart. Aside from the effect on mitochondrial autophagy, whether or not the lack of appropriate fission in Drp1-hetCKO mice also contributes to the enhancement of HF in these mice during PO remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload–Induced Mitochondrial Dysfunction and Heart Failure

et al. 2016

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Background Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Methods and Results Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure (HF) was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Mito-Keima, was transiently activated around 3–7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and HF after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on Day 7 after TAC partially rescued mitochondrial autophagy, and attenuated mitochondrial dysfunction and HF induced by pressure overload (PO). Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Conclusions Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to PO. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and HF, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during PO.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload–Induced Mitochondrial Dysfunction and Heart Failure

et al. 2016

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“…This apparent discrepancy, together with our observations that inhibiting fusion or fission individually does not affect lifespan in C. elegans , may indicate an evolutionary shift in the effects of altered mitochondrial morphology on lifespan. Furthermore, recent work performed in mice demonstrated that concomitant deletion of Mfn1 in Mff mutant (fission-deficient) mice restores mitochondrial network balance and leads to rescue of mitochondrial function and tissue integrity (Chen et al, 2015). Our data further show that co-inhibiting fusion and fission increases FAO capacity in mammalian cells, which is required for drp-1;fzo-1 longevity.…”

Section: Discussionmentioning

confidence: 99%

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

et al. 2017

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Summary Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

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“…Several studies have concluded that Mff is the major receptor for Drp1 (Liu and Chan, 2015;Loson et al, 2013;Otera et al, 2010); however, the degree of mitochondrial elongation in ΔMff MEFs was similar to that seen in ΔMiD51 or ΔMiD49/51 MEFs. Recently, it has been found that mice lacking Mff can live for up to 13 weeks and eventually die from cardiomyopathy due to mitochondrial fission defects (Chen et al, 2015). This phenotype is significantly milder than the embryonic lethality seen for Drp1-knockout mice (Ishihara et al, 2009;Wakabayashi et al, 2009), suggesting that mitochondrial fission can take place in other tissues lacking Mff (Chen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been found that mice lacking Mff can live for up to 13 weeks and eventually die from cardiomyopathy due to mitochondrial fission defects (Chen et al, 2015). This phenotype is significantly milder than the embryonic lethality seen for Drp1-knockout mice (Ishihara et al, 2009;Wakabayashi et al, 2009), suggesting that mitochondrial fission can take place in other tissues lacking Mff (Chen et al, 2015). Mff might also play an important role in neurons given its ability to efficiently stimulate the GTPase activity of the brainspecific Drp1 isoform compared to the ubiquitously expressed isoform (Macdonald et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission

Osellame

Singh

Stroud

et al. 2016

Journal of Cell Science

246

272

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Cytosolic dynamin-related protein 1 (Drp1, also known as DNM1L) is required for both mitochondrial and peroxisomal fission. Drp1-dependent division of these organelles is facilitated by a number of adaptor proteins at mitochondrial and peroxisomal surfaces. To investigate the interplay of these adaptor proteins, we used geneediting technology to create a suite of cell lines lacking the adaptors MiD49 (also known as MIEF2), MiD51 (also known as MIEF1), Mff and Fis1. Increased mitochondrial connectivity was observed following loss of individual adaptors, and this was further enhanced following the combined loss of MiD51 and Mff. Moreover, loss of adaptors also conferred increased resistance of cells to intrinsic apoptotic stimuli, with MiD49 and MiD51 showing the more prominent role. Using a proximity-based biotin labeling approach, we found close associations between MiD51, Mff and Drp1, but not Fis1. Furthermore, we found that MiD51 can suppress Mff-dependent enhancement of Drp1 GTPase activity. Our data indicates that Mff and MiD51 regulate Drp1 in specific ways to promote mitochondrial fission.

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Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy

Abstract: Mice deficient for mitochondrial fission factor (Mff) die from severe cardiomyopathy, but cardiac function, tissue integrity, and mitochondrial respiration are robustly rescued by rebalancing mitochondrial dynamics through deletion of Mitofusin 1 (Mfn1).

Cited by 137 publications

References 32 publications

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload–Induced Mitochondrial Dysfunction and Heart Failure

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload–Induced Mitochondrial Dysfunction and Heart Failure

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission

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