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Figure 5. Mitochondrial defects in the hypertrophic cardiomyopathy (HCM) heart. Mitochondrial ultrastructure in the HCM heart is characterized by fragmentation and disorganization relative to the myofilaments. Dampening of mitophagy and mitochondrial biogenesis underlie impaired mitochondrial quality control. Functionally, mitochondria in HCM exhibit defects in fatty acid oxidation capacity, total oxidative phosphorylation (OXPHOS) capacity, and nicotinamide adenine dinucleotide (NADH)-linked respiration, which are strongly linked to cardiac remodeling in genotype-negative (G-) patient tissue. Respiratory impairment may be caused by NAD depletion, impaired supercomplex formation, and lower levels of OXPHOS proteins. Impaired Ca²⁺ homeostasis due to perturbed crosstalk between the sarcoplasmic reticulum (SR) and mitochondria and disproportional loading of Ca²⁺ to the mitochondria relative to the myofilaments further affect mitochondrial respiration and redox defense. Reduced mitochondrial protein synthesis and impaired maintenance of mitochondrial DNA (mtDNA) may additionally impact overall mitochondrial homeostasis. Dysfunction of the creatine kinase shuttle thwarts efficient energy provision to the myofilaments and compromises ADP buffering capacity. Created in BioRender. Nollet E (2025) https://BioRender.com/cnpuycj. TCA: Tricarboxylic acid cycle; ADP: adenosine diphosphate; ATP: adenosine triphosphate; FAD: flavin adenine dinucleotide; NAD: nicotinamide adenine dinucleotide; SDH: succinate dehydrogenase; CI: complex I; CII: complex II; CIII: complex III; CIV: complex IV; ETFDH: electron-transferring-flavoprotein dehydrogenase; CETF: electron transfer flavoprotein complex.