Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

Abstract

Summary Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence.

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Indeed, studies indicate suppression of mitophagy with prolonged cardiac stress, such as pressure overload, which can be rescued by stimulating autophagosome formation with Tat-Beclin-1 transduction (196) or enhancing AMPK2α-mediated PINK1 phorphorylation (225). Molecular players that mediate mitochondrial dynamics, namely mitofusins (MFN1 and MFN2) that mediate mitochondrial fusion; and Drp1, that mediates mitochondrial fission, play a critical role in maintaining mitochondrial quality control and regulating mitophagy in the heart (201, 203). Mitochondrial fission via Drp-1 was shown to be essential for basal mitophagy and heterozygous disruption of Drp1 in cardiac myocytes was sufficient to induce cardiomyopathic dysfunction with fasting (91), indicating a critical need for mitophagy under nutrient deprivation conditions (55).…”

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

“…21,[25][26][27] Therefore, mitochondria represent a potential therapeutic target. 16 In most clinical pathology, excessive mitochondrial fragmentation is observed, which is mediated by either profusion factor mfn2 deficiency or profission factor Drp1 hyperactivation, thus Mfn2 activation or Drp1 inhibition arising as a potential therapeutic target for mitochondrial dynamics emendation. 28 Mitochondrial fusion and fission play a critical role in mitochondria functional quality control, in which dysfunctional mitochondrial will be ultimately eliminated by autophagy and replaced by mitochondrial biogenesis for 3,29 Recent data indicate that perturbation between mitochondrial fusion or fission is more deleterious than the simultaneous abrogation of both processes.…”

“…35 Indeed, Drp1 deletion increased the mitochondrial calcium uptake through upregulating MCU and MICU1 expression. 16,17,41 Additionally, Mfn1 expression can protect the heart against ischemia-reperfusion injury. 36,37 Mfn 2 and Drp1 have other functional roles in addition to fission and fusion.…”

“…16 Thus, the better safe strategy for correcting mitochondrial dynamism is to enhance dynamism factors expression other than inhibits dynamism factors, so far, the redundant dynamism factors are not deleterious to hearts. 16 Thus, the better safe strategy for correcting mitochondrial dynamism is to enhance dynamism factors expression other than inhibits dynamism factors, so far, the redundant dynamism factors are not deleterious to hearts.…”

“…9,10 To avoid being eliminated, the healthy mitochondria will reenter the mitochondrial pool through mitochondrial fusion in which Mfn1/Mfn2 mediate outer membrane fusion, and OPA1 subsequently mediates inner membrane fusion. 16,17 Therefore, mitochondria fusion promotion is necessary and represents a potential therapeutic strategy for restoring mitochondrial fusion. 13 Biology still follows a principle of "Broken is easier than repair."…”