Systemic Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Haploinsufficiency via Potential Inter-Organ Crosstalk.

Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout () and a whole-body heterozygous knockout (). Despite similar reductions in mRNA expression in the hearts, mice exhibited no cardiac dysfunction, whereas mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as , , , and , increased mitochondrial dynamics (, ), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator , all occurring without overt structural remodeling. These alterations were absent in hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of -mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling.