Understanding Cardiac Mitochondrial Quality Control Through the Lens of Barth Syndrome

Robust mitochondrial quality control via mitophagy is necessary in cardiomyocytes (CMs) to maintain the efficient energy production needed for contraction, calcium regulation, substrate production and response to stress. As such, CMs utilize a repertoire of canonical and non-canonical mitophagy responses to ensure mitochondrial quality and function. Unsurprisingly, malfunctioning, hypoactive and hyperactive mitophagy contribute to cardiac pathologies from fetal development through adulthood. We propose to study the effects of impairments of canonical mitophagy in the heart in the setting of TAFAZZIN (TAZ) deficiency. TAZ deficiency underlies the X-linked disorder, Barth Syndrome (BTHS), which is a multisystem disorder with a cardiac phenotype of left ventricular noncompaction, early-onset cardiac dysfunction, and a lifelong risk of acute cardiac decompensation. BTHS represents a uniquely relevant platform to study the role of mitophagy in the heart because interaction between cardiolipin (CL), the defective molecule in BTHS, and LC3, a central mediator of canonical mitophagy, is required for at least some forms of canonical mitophagy. In our preliminary studies we developed iPSC-derived TAZ-deficient cardiomyocytes (TAZ-KO iPSC-CMs) and TAZ-KO mice. We found that TAZ-KO iPSC-CMs present with abnormal mitochondrial morphology and impairments of canonical mitophagy, indicated by abnormal expression of mitophagy-associated genes and altered response to mitophagy triggers. In TAZ-KO mice, we found mitophagy to be implicated in the severity of cardiomyopathy. Therefore, our central hypothesis is: Dysregulation of canonical mitophagy is of fundamental importance to the pathogenesis of dysfunction of the TAZ-deficient heart. This defective mitophagy ultimately causes abnormal CM differentiation, response to stress, and bioenergetic capacity, all of which are characteristic cardiac phenotypes in BTHS. We will investigate the following questions using 2 complementary models, TAZ-iPSC CMs and the TAZ-KO mouse via the following aims: 1) To evaluate the effect of TAZ deficiency on mechanisms of mitochondrial quality control; 2) To determine effects of TAZ deficiency on canonical mitophagy in CM development and maturation; 3) To study differences in mitophagy and heart function between TAZ-KO mice in two different genetic backgrounds with divergent cardiac phenotypes to understand targets for mitophagy modification. Understanding the role of impairments to canonical mitophagy in BTHS will provide insights into mechanisms of mitochondrial quality control in the heart, show how disrupted mitophagy affects cardiomyocyte bioenergetics and homeostasis, and elucidate the underlying pathogenesis of Barth Syndrome. Project Number: 5R01HL175954-02 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Hilary Vernon (+2 co-PIs) | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $648,582 | Activity Code: R01 | Study Section: Therapeutic Approaches to Genetic Diseases Study Section[TAG] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R01HL17595402