DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

Favaro, Giulia; Romanello, Vanina; Varanita, Tatiana; Desbats, María Andrea; Morbidoni, Valeria; Tezze, Caterina; Albiero, Mattia; Canato, Marta; Gherardi, Gaia; Stefani, Diego De; Mammucari, Cristina; Blaauw, Bert; Boncompagni, Simona; Protasi, Feliciano; Reggiani, Carlo; Scorrano, Luca; Salviati, Leonardo; Sandri, Marco

doi:10.1038/s41467-019-10226-9

Cited by 321 publications

(359 citation statements)

References 61 publications

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“…These studies suggest that PRKAR1A deficiency diminished cardiomyocyte hypertrophy in vitro, likely through inactivation of Drp1. It has been shown that loss of Drp1 activity suppresses cardiac hypertrophy and reduces skeletal muscle mass in vivo (Favaro et al, 2019; Hasan et al, 2018). Although phospho‐Drp1 (S637) was undetectable in the heart at 3 months of age (data not shown), it cannot be excluded that ablation of PRKAR1A might enhance Drp1 S637 phosphorylation during early cardiac development.…”

Section: Discussionmentioning

confidence: 99%

PRKAR1A deficiency impedes hypertrophy and reduces heart size

et al. 2020

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Protein kinase A (PKA) activity is pivotal for proper functioning of the human heart, and its dysregulation has been implicated in a variety of cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity by sequestering PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) in early adulthood, and may die later in life from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart development. Here, we showed that left ventricular mass was reduced in young CNC patients with PRKAR1A mutations or deletions. Cardiac‐specific heterozygous ablation of PRKAR1A in mice increased cardiac PKA activity, and reduced heart weight and cardiomyocyte size without altering contractile function at 3 months of age. Silencing of PRKAR1A, or stimulation with the PKA activator forskolin completely abolished α1‐adrenergic receptor‐mediated cardiomyocyte hypertrophy. Mechanistically, depletion of PRKAR1A provoked PKA‐dependent inactivating phosphorylation of Drp1 at S637, leading to impaired mitochondrial fission. Pharmacologic inhibition of Drp1 with Mdivi 1 diminished hypertrophic growth of cardiomyocytes. In conclusion, PRKAR1A deficiency suppresses cardiomyocyte hypertrophy and impedes heart growth, likely through inhibiting Drp1‐mediated mitochondrial fission. These findings provide a potential novel mechanism for the cardiac manifestations associated with CNC.

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Section: Discussionmentioning

confidence: 99%

PRKAR1A deficiency impedes hypertrophy and reduces heart size

et al. 2020

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“…The calcium and ROS signaling are always crosstalk within mitochondrial microdomains, and mitochondrial calcium is a stimulator of mitochondrial superoxide production in cardiomyocytes. 40 However, the Mfn2-dependent mitochondrial-SR interfaces do not change, indicating that inter-organelle tethering by Mfn2 expression or Drp1 deletion was not perturbed in hearts. Moreover, the intramitochondrial calcium waves or/and superoxide can also stimulate mPTP opening.…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction

Qin

Liu

et al. 2019

The FASEB Journal

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Mitochondrial fusion and fission are essential for heart function. Abrogating mitochondrial dynamism leads to cardiomyopathy. Excessive mitochondrial fragmentation is involved in most heart diseases, thus enhancing mitochondrial fusion will be a potential therapeutic strategy. To understand the effects of promoting mitochondrial fusion in adult cardiac, we investigated mice hearts, and cultured murine embryonic fibroblasts (MEFs), in which mitofusin 2 (Mfn2) overexpressed or dynamin-related protein 1 (Drp1) was abrogated concomitantly forcing mitochondrial fusion. Parallel studies revealed that fission-defective Drp1 knockout hearts and MEFs evoked stronger mitochondrial enlargement, enhanced mitophagy with mitochondrial volume decrease and increased mitochondrial calcium uptake, superoxide production, and permeability transition pore opening, contributed to cardiomyocyte apoptosis and dilated cardiomyopathy. Mfn2 overexpression in the adult heart is comparable with the control except for slight mitochondrial enlargement and mitochondrial volume increase, but without mitophagy induction. Moreover, Mfn2 overexpression increases mitochondrial biogenesis and fusion could protect against mitochondrial fragmentation and Drp1 deletion evoking mitophagy in MEFs. Our findings indicate that mitochondrial fusion provoked by fusion promotion and fission inhibition direct the different fate of heart, Mfn2 upregulation other than Drp1 downregulation well maintains heart mitochondrial function is a more safe strategy for correcting excessive mitochondrial fragmentation in hearts. K E Y W O R D Sadult heart, cardiac function, mitochondrial dynamics, mitochondrial fitness, therapeutic target 664 | QIN et al

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“…Not many studies have addressed how Drp1 modulation affects the mitochondrial Ca 2+ buffering capacity. Drp1 deficiency in myofibers (Favaro et al, 2019) and macrophages (Wang et al, 2017) increases mitCa 2+ levels. Here we observe the opposite effect, suggesting that the role of Drp1 on mitCa 2+ regulation may be context dependent.…”

Section: Resultsmentioning

confidence: 99%

Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing

Ponte

Carvalho

Gagliardi

et al. 2019

Preprint

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Mitochondria adapt to cellular needs by changes in morphology through fusion and fission events, referred to as mitochondrial dynamics. Mitochondrial function and morphology are intimately connected and the dysregulation of mitochondrial dynamics is linked to several human diseases. In this work, we investigated the role of mitochondrial dynamics in wound healing in the Drosophila embryonic epidermis. Mutants for mitochondrial fusion and fission proteins fail to close their wounds, indicating that the regulation of mitochondrial dynamics is required for wound healing. By live-imaging, we found that loss of function of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) compromises the increase of cytosolic and mitochondrial calcium upon wounding and leads to F-actin defects at the wound edge, culminating in wound healing impairment. Our results highlight a new role for mitochondrial dynamics in the regulation of calcium and F-actin during epithelial repair.SummaryWe show that mitochondrial dynamics proteins are required for epithelial repair. In particular, Drp1 loss-of-function leads to defects in the dynamics of cytosolic and mitochondrial calcium and F-actin upon wounding.

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DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

Cited by 321 publications

References 61 publications

PRKAR1A deficiency impedes hypertrophy and reduces heart size

PRKAR1A deficiency impedes hypertrophy and reduces heart size

Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction

Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing

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