Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand

Abstract

These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.

RhoA regulates Drp1 mediated mitochondrial fission through ROCK to protect cardiomyocytes

“…Thus in the setting of exercise, Drp1 dependent fission serves as an adaptive physiological response to enhance mitochondrial function. Notably the fission observed with exercise is not associated with mitochondrial depolarization and concurrent cardiomyocyte cell death [39]. Likewise, activation of RhoA to levels used in the current study does not lead to mitochondrial membrane depolarization or increased opening of the mitochondrial permeability transition pore [45] and S1P stimulation preserves mitochondrial membrane potential in cardiomyocytes under oxidative stress [9].…”

“…Mitochondrial Drp1 was also increased in both cardiomyocytes and isolated hearts treated with S1P. GPCR pathways previously reported to stimulate Drp1 translocation to the mitochondria are the Gα s coupled β-adrenergic [35, 39] and the Gα q coupled α-adrenergic [40] receptors. Notably, studies showing responses to agonists for these other GPCRs in primary cardiomyocytes have examined changes in Drp1 phosphorylation, localization, or function after 6–48 h of stimulation, when additional signaling cascades or changes in gene expression could be activated [35, 40].…”

“…This is consistent with studies in which heterozygous cardiac Drp1 knockout mice were reported to have increased infarct from I/R [23] and increased apoptosis following pressure overload [44], suggesting that Drp1 serves a protective function in the response to these interventions. Inhibiting Drp1 dependent fission in cardiomyocytes during exercise was also recently shown to prevent β-adrenergic receptor mediated increases in mitochondrial respiration capacity [39]. Thus in the setting of exercise, Drp1 dependent fission serves as an adaptive physiological response to enhance mitochondrial function.…”

Mitochondrial remodeling: Rearranging, recycling, and reprogramming

“…Cardiac mitochondrial biogenesis has been demonstrated in chronic exercise conditioning (110, 111). Our preliminary data in the heart suggest that mitochondrial fission may be a component of the normal adaptation to increased energetic demand, such as occurs during exercise, a process we call “physiologic fragmentation” (112). In contrast to pathologic fragmentation, exercise-induced fragmentation is associated with normal or enhanced, rather than degraded, mitochondrial function, maintenance of normal Δψm and ROS production, and repression, rather than activation, of mitophagy.…”

“…As well, increasing Ca 2+ increases mitochondrial fragmentation (128) through calcineurin (removing an inhibitory phosphate on Drp1) or CaMK (phosphorylating Ser600) (21, 129). This process, although generally associated with pathologic stress, may also play a role in the response to normal physiologic stresses (see below (112)). In contrast, excessive Ca 2+ opens the MPTP and can trigger cell death (36), highlighting the danger of excessive Ca 2+ , a consequence of chronic β-AR signaling in diseases such as heart failure (130).…”