Targeting Mitochondrial Metabolism in Heart Failure: From Genetic Drivers to Fuel Modulation Therapies

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Despite therapeutic advances, the condition continues to perplex clinicians due to its complex metabolic underpinnings. In recent years, research illuminates how disruptions in mitochondrial function and metabolic flexibility contribute to HF progression and the therapeutic potential of metabolic modulation through agents such as sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and exogenous ketones.

Emerging data presented at the American Heart Association 2025 Scientific Sessions reveal how mitochondrial genetics and energy substrate regulation intersect to influence disease susceptibility and treatment response.

Mitochondrial Genetics and Sex Differences in Cardiac Bioenergetics

A crucial piece of this evolving understanding comes from population-based systems genetics research exploring how genetic variation governs mitochondrial function and its link to HF. Using multiple inbred mouse populations—including the Hybrid Mouse Diversity Panel (HMDP), Diversity Outbred (DO), and BXD cohorts—investigators analyzed both transcriptomic and proteomic data to identify key regulators of mitochondrial gene expression and oxidative metabolism.¹

Through this comprehensive approach, chromosome 17 emerged as a major determinant of mitochondrial protein abundance. LRPPRC (leucine-rich pentatricopeptide repeat-containing protein) was identified as a pivotal gene controlling mitochondrial RNA stability and translation—critical steps in oxidative phosphorylation. Mice with reduced LRPPRC activity exhibited widespread mitochondrial transcript instability, diminished oxidative function, and increased susceptibility to cardiac dysfunction.¹

“We found that the locus on chromosome 17 is mediated by LRPPRC, and that increased expression of this gene is associated with greater mitochondrial abundance and enhanced oxidative metabolism,” explained Karthickeyan Chella Krishnan, PhD, assistant professor at the University of Cincinnati.¹

Sex-specific differences in mitochondrial biogenesis and function were also observed across genetic backgrounds. Male and female mice displayed distinct patterns of mitochondrial content and respiratory capacity, suggesting that hormonal or chromosomal influences modulate cardiac energy metabolism.¹

“There are clear sex differences in mitochondrial function—females tend to be protected, but this protection is lost after menopause,” said Krishnan.¹

These findings raise important clinical questions about whether sex-linked variations in mitochondrial regulation could partially explain the differing prevalence, phenotype, and treatment response observed in men and women with HF.¹

Metabolic Flexibility in the Healthy and Failing Heart

A healthy heart is highly adaptive and adjusts substrate use based on nutrient availability and energetic demand, drawing primarily from fatty acid oxidation under normal conditions and shifting to glucose utilization during stress. This metabolic flexibility allows the myocardium to maintain ATP generation efficiently across a wide range of physiologic states.¹

“Basically, the mammalian heart is a metabolic omnivore,” said Krishnan, “and as we all know, metabolic flexibility is a defining feature of myocellular homeostasis."¹

However, in patients with HF, this adaptability is lost. Chronic pressure or volume overload, neurohormonal activation, and mitochondrial dysfunction collectively impair oxidative metabolism. Over time, this leads to bioenergetic failure.¹

“During times of stress and in the failing heart, the heart switches from mitochondrial oxidative metabolism and fatty acid oxidation to glycolysis and use of glucose for CRISPR as its primary fuel source,” explained Svati H. Shah, MD, MHS, from Duke University Medical Center.¹

Understanding these shifts reframes HF as a disorder of hemodynamics and cellular metabolism. This recognition has spurred therapeutic strategies aimed at restoring metabolic flexibility and enhancing mitochondrial performance.¹

SGLT2 Inhibitors and Endogenous Ketosis

Among these metabolic modulators, SGLT2 inhibitors have generated substantial interest beyond their glycemic effects. In landmark trials such as DEFINE-HF (NCT02653482)² and PRESERVED-HF (NCT03030235),³ these agents improved clinical outcomes and functional status in both reduced and preserved ejection fraction HF phenotypes.¹

Metabolomic analyses shed light on the mechanisms underlying these benefits. Treatment with SGLT2 inhibitors appears to induce a state of mild endogenous ketosis, elevating circulating β-hydroxybutyrate levels.¹

“Ketone bodies may actually be better fuels,” Shah explained. “They yield more adenosine triphosphate [ATP] per unit of oxygen consumed than glucose or fatty acids, and so they can help relieve these metabolic bottlenecks and heart failure."¹

Furthermore, ketone metabolism has been associated with reduced oxidative stress, improved mitochondrial respiration, and modulation of inflammatory signaling—all of which contribute to improved cardiac energetics and remodeling. For pharmacists, understanding this mechanism reinforces the importance of these agents not only in diabetes care but also as cornerstone therapies in comprehensive HF management.¹

GLP-1 Receptor Agonists

Beyond their effects on glucose control and weight reduction, GLP-1 receptor agonists have also been implicated in cardiac metabolic modulation. Preclinical studies indicate that GLP-1 signaling enhances fatty acid oxidation and mitochondrial biogenesis while reducing myocardial inflammation and oxidative stress.¹

Clinical observations have been mixed regarding their direct impact on HF outcomes, but emerging data suggest potential synergy when used in combination with SGLT2 inhibitors. The ability of GLP-1 receptor agonists to influence both systemic and myocardial metabolism positions them as promising adjuncts in the metabolic management of HF—particularly among patients with comorbid obesity or diabetes.¹

Implications for Pharmacists

For pharmacists, this expanded understanding of cardiac metabolism has several clinical implications. First, recognizing the metabolic effects of drugs like SGLT2 inhibitors and GLP-1 receptor agonists allows for more informed counseling and monitoring, particularly regarding volume status, renal function, and potential additive effects when therapies overlap. Second, pharmacists are well positioned to educate patients and multidisciplinary teams about the mechanistic rationale behind these agents—framing them not only as glucose-lowering drugs but also as modulators of mitochondrial efficiency and energy substrate use.

As HF management evolves toward more metabolically targeted approaches, pharmacists will play a crucial role in bridging basic science and clinical application—translating complex molecular insights into practical, patient-centered care.

REFERENCES

1. Ge Y, Vondriska T, Krishnan K, et al. Heart Failur-omics: Understanding as Many as Possible Aspects of the Most Lethal Disease. Presented at: American Heart Association 2025 Scientific Sessions. November 7-10, 2025. New Orleans, Lousiana

2. Dapagliflozin effect on symptoms and biomarkers in patients with heart failure (DEFINE-HF). Clinicaltrials.gov. Updated April 21, 2022. Accessed November 7, 2025. https://clinicaltrials.gov/study/NCT02653482

3. Dapagliflozin in PRESERVED ejection fraction heart failure (PRESERVED-HF). Clinicaltrials.gov. Updated October 19, 2022. Accessed November 7, 2025. https://clinicaltrials.gov/study/NCT03030235