Heart Hormone FGF21 Fights Cardiac Hypertrophy by Clearing Damaged Mitochondria
FGF21 activates PINK1-driven mitophagy to remove dysfunctional mitochondria, protecting the heart from hypertrophy and failure.
Summary
Researchers have uncovered a key mechanism by which the hormone FGF21 protects against cardiac hypertrophy: it activates PINK1-mediated mitophagy, a cellular housekeeping process that removes damaged mitochondria. Using mouse models of pressure-overload (TAC surgery) and cell-based phenylephrine stress, the team showed that FGF21 knockout worsened mitochondrial dysfunction and cardiac decline, while FGF21 treatment restored mitophagy and cardiac function in a PINK1-dependent manner. Crucially, the study also found that FGFR1—the receptor through which FGF21 signals—becomes downregulated as heart failure progresses, potentially explaining why rising FGF21 levels in failing hearts fail to protect them.
Detailed Summary
Cardiac hypertrophy—pathological enlargement of the heart—is a leading precursor to heart failure, responsible for substantial cardiovascular morbidity and mortality. While FGF21 levels are known to rise in patients with cardiac hypertrophy, this endogenous increase apparently fails to halt progression to overt heart failure. This study set out to explain why FGF21 can be cardioprotective yet insufficient, and to delineate the mitochondrial pathway involved.
Using transverse aortic constriction (TAC) in mice as an in vivo pressure-overload model, and phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) as an in vitro model, the researchers compared outcomes in wild-type, Fgf21 knockout (Fgf21−/−), and Pink1 knockout (Pink1−/−) animals. Cardiac function was assessed by echocardiography; mitochondrial health was evaluated by transmission electron microscopy, ATP assays, TMRM staining, ROS measurement, and OXPHOS protein expression. Mitophagy was tracked via LC3, PINK1, Parkin, p62, and co-localization studies using MitoTracker and LysoTracker imaging.
Fgf21−/− TAC mice showed dramatically worsened cardiac function (reduced ejection fraction and fractional shortening), greater cardiomyocyte enlargement, more myocardial fibrosis, lower ATP production, elevated ROS, and severely impaired mitophagy compared with wild-type TAC mice. In vitro, FGF21 siRNA knockdown amplified PE-induced hypertrophy and mitophagy dysfunction. Conversely, exogenous FGF21 protein (efruxifermin) treatment in both TAC and PE models enhanced mitophagy markers and improved mitochondrial quality—but these benefits were completely abolished when PINK1 was knocked out, establishing PINK1 as the critical downstream mediator. Pharmacological rescue experiments using rapamycin (an mTOR inhibitor that boosts autophagy) or PMI (a p62-mediated mitophagy inducer) in Fgf21−/− TAC mice restored mitophagy flux, improved cardiac function, and reduced hypertrophic remodeling, confirming that mitophagy enhancement alone is sufficient to compensate for FGF21 deficiency.
A pivotal secondary finding concerns FGFR1, the primary receptor for FGF21 in the heart. The study found that while FGF21 expression rises during hypertrophy and heart failure, FGFR1 expression moves in the opposite direction—declining as disease progresses. Knockdown of FGFR1 (but not FGFR3) in NRCMs abolished FGF21-induced mitophagy enhancement. This receptor-ligand mismatch provides a mechanistic explanation for why endogenously elevated FGF21 fails to protect the failing heart: its receptor is progressively lost.
These findings position the FGF21→FGFR1→PINK1→mitophagy axis as a tractable therapeutic target. Strategies that either deliver exogenous FGF21 early in hypertrophy (before FGFR1 is lost), restore FGFR1 expression, or directly boost PINK1-mediated mitophagy pharmacologically may offer novel approaches to preventing the hypertrophy-to-heart-failure transition.
Key Findings
- FGF21 knockout worsened TAC-induced cardiac dysfunction, fibrosis, ROS accumulation, and mitophagy impairment in mice.
- FGF21's cardioprotective mitophagy effects are entirely PINK1-dependent; PINK1 knockout abolished FGF21 benefits.
- Rapamycin and the mitophagy inducer PMI rescued cardiac function in FGF21-deficient TAC mice by restoring mitophagy.
- FGFR1 expression declines as heart failure progresses, inversely mirroring rising FGF21 levels—explaining therapeutic resistance.
- FGFR1 knockdown (not FGFR3) blocked FGF21-mediated mitophagy, identifying FGFR1 as the essential receptor.
Methodology
The study used surgical TAC in wild-type, Fgf21−/−, and Pink1−/− C57BL/6 mice alongside PE-treated neonatal rat cardiomyocytes to model cardiac hypertrophy in vivo and in vitro. Cardiac function was measured by echocardiography; mitochondrial health and mitophagy were assessed by TEM, ATP assays, TMRM/MitoTracker/LysoTracker imaging, western blot, and LC3 autophagosome quantification. Pharmacological interventions included exogenous FGF21 (efruxifermin), rapamycin, and PMI to dissect and rescue the mitophagy pathway.
Study Limitations
The study relies primarily on murine TAC and neonatal rat cardiomyocyte models, which may not fully recapitulate human cardiac hypertrophy dynamics or the kinetics of FGFR1 loss in patients. Mechanistic details connecting FGFR1 activation to PINK1 upregulation (e.g., intermediate signaling steps) remain incompletely characterized. Long-term safety and efficacy of mitophagy induction strategies such as rapamycin in the cardiac context were not evaluated.
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