. Author manuscript; available in PMC: 2023 Oct 18.

Published in final edited form as: Nat Rev Cardiol. 2022 May 6;19(11):723–736. doi: 10.1038/s41569-022-00703-y

Table 1 |.

Systemic and cardiac-specific genetic mouse models of mitochondrial dynamics

Target(s)	Genetic model	Outcome		Refs
Target(s)	Genetic model	Basal characterization	Effects of pathological stress	Refs
Mff	Systemic homozygous knockout	Lethal cardiomyopathy at 13 weeks. Neuromuscular and fertility defects. Impaired mitochondrial respiration and ATP production. Loss of pro-fusion MFN1 rescues phenotype.	NR	³⁴
Dnm1l	Systemic homozygous knockout	Lethality by embryonic day 10.5. Developmental defects due to brain hypoplasia and apoptosis.	NR	^28,29
	Systemic heterozygous knockout	Viable with no obvious cardiac phenotype.	Reduced immune infiltration and protection against angiotensin II-mediated AAA. No effect in AAV9–PCSK9 atherosclerosis model. Protection against TNF-driven endothelial leukocyte adhesion.	^{12,29,147,155}
	Systemic C452F mutation	Progressive cardiac mitochondrial dysfunction and sterile inflammation resulting in heart failure.	NR	⁹²
	Cardiac-specific homozygous knockout	Lethal dilated cardiomyopathy by postnatal day 7. Cardiac mitochondrial respiratory defects, mitophagy impairment and mtDNA nucleoid aggregation.	NR	^30–32
	Cardiac-specific heterozygous knockout	Normal cardiac structure and function despite reduced mitochondrial ATP production.	Increased myocardial IRI. Impaired mitophagy and exacerbated cardiac pathophysiology following pressure overload.	^8,31,90
	Tamoxifen-inducible, cardiac-specific knockout	Lethal dilated cardiomyopathy at 4–8 weeks post-tamoxifen. Mitochondrial dysfunction evident prior to cardiac pathophysiology. Dysregulation of mitophagy and activation of apoptosis in the heart. Diminished maximal exercise performance.	NR	^3,8,32,79
	Systemic, doxycycline-inducible, K38A dominant negative transgenic	No phenotype evident after modest induction of transgene for 6 months.	Protection against diabetes-induced oxidative stress in the kidney and liver. Protection against vascular hyperplasia following arterial injury.	^33,154
	Cardiac-specific inducible bitransgenic (tetracycline-off)	Normal mitochondrial and cardiac function.	NR	⁴¹
Mfn1	Systemic homozygous knockout	Lethality by embryonic day 11.5.	NR	³⁶
Mfn2	Systemic homozygous knockout	Lethality by embryonic day 10.5.	NR	³⁵
Mfn1, Mfn2	Cardiac-specific double homozygous knockout	Lethality by embryonic day 9.5 when Cre recombinase expression is driven by the NKX-2.5 promoter. Lethal cardiomyopathy when cre expression is driven by the MYH6 promoter. Abnormal mitochondrial structure and reduced mtDNA content.	NR	^37,38
Mfn1, Mfn2	Tamoxifen-inducible, cardiac-specific double knockout	Eccentric ventricular remodelling and wall thickening at 6 weeks after gene deletion. Reduced mitochondrial size and activation of the mitochondrial unfolded protein response. 50% premature mortality by 9 weeks post-tamoxifen.	Protection against myocardial IRI when induced ~4 weeks after gene deletion (prior to cardiomyopathy) due to impaired mitochondria-sarcoplasmic reticulum tethering.	^32,41,170
Dnm1l, Mfn1, Mfn2	Tamoxifen-inducible, cardiac-specific triple knockout	Concentric cardiac hypertrophy eventually progressing to heart failure, despite minimal changes in myocyte viability. Extended survival with mfn1-mfn2-dnml1 triple knockout compared with mfn1-mfn2 double knockout or dnm1l single knockout (7 vs 17 weeks post-tamoxifen).	NR	⁴¹

AAA, abdominal aortic aneurysm; AAV9, adeno-associated virus serotype 9; DNM1L, dynamin-1-like protein (also known as dynamin-related protein 1 (DRP1)); IRI, ischaemia–reperfusion injury; mtDNA, mitochondrial DNA; MFN, mitofusin; MYH6, myosin-6; NKX-2.5, homeobox protein Nkx-2.5; NR, not reported; PCSK9, proprotein convertase subtilisin/kexin type 9; TNF, tumour necrosis factor.