Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism

TL;DR

Deleting the Immt gene in mouse hearts disrupts mitochondrial structure and metabolism, but a stress response temporarily preserves heart function.

Contribution

Heart-specific deletion of Immt reveals its essential role in mitochondrial structure and metabolism, and identifies a compensatory stress response.

Findings

Deleting the Immt gene in mouse hearts leads to severe mitochondrial structural abnormalities and heart failure.

Loss of Immt triggers a mitochondrial stress response that temporarily preserves metabolic function.

The heart shifts to using glucose, ketones, and amino acids when mitochondria are dysfunctional.

Abstract

What are the main findings?
The Immt gene (Mic60) is required in the mouse heart to maintain mitochondrial structure and function.Loss of mitochondria in the heart is eventually lethal, although compensation and temporary metabolic function are preserved by a unique mitochondrial stress response.

The Immt gene (Mic60) is required in the mouse heart to maintain mitochondrial structure and function.

Loss of mitochondria in the heart is eventually lethal, although compensation and temporary metabolic function are preserved by a unique mitochondrial stress response.

What are the implications of the main findings?
Inducible loss of Mic60 in the heart can be used as a model to investigate mitochondrial renewal and biogenic programs in vivo.Inducible loss of Mic60 in the heart can also suggest novel metabolic pathways that are induced in the heart to compensate for the loss of mitochondrial oxidative function.

Inducible loss of Mic60 in the heart can be used as a model to investigate mitochondrial renewal and biogenic programs in vivo.

Inducible loss of Mic60 in the heart can also suggest novel metabolic pathways that are induced in the heart to compensate for the loss of mitochondrial oxidative function.

Mitochondria comprise ~1/3rd of the volume of an adult ventricular cardiomyocyte. The gene Immt encodes the Mic60/Mitofilin protein that is hypothesized to organize the mitochondrial contact site and cristae organization system (MICOS) complex that generates mitochondrial cristae junctions between the inner and outer membranes. To investigate the function of the Immt gene in the mouse heart, we generated and characterized mice in which this gene was specifically deleted in the mouse heart using a loxP-targeted allele (Immtfl/fl) and either the constitutive heart-specific Myh6-Cre transgene or the conditional Myh6-MerCreMer transgene, each of which showed lethality in several weeks. Hearts from these mice showed progressive hypertrophic cardiomyopathy and failure with lost contractility and lung edema. At the ultrastructural level, hearts from these mice showed extreme abnormalities in mitochondrial architecture characterized by lost cristae junctions, stacking of the inner mitochondrial membranes, mitophagy and areas with complete absence of mitochondria. Analysis of mitochondria showed loss of the MICOS complex of proteins as well as loss of mitochondrial membrane potential (Δψ) and increased expression of mitophagy proteins and mitochondrial biogenesis transcription factors. Hearts from these mice also showed widespread cardiomyocyte necrosis and induction of the universal mitochondrial stress response at the mRNA level, as well as major alterations in cardiac metabolites, suggesting greater use of glucose, ketones and amino acids. We conclude that the Immt gene is required for cardiac mitochondrial structure and function, although the ensuing mitochondrial stress response provides molecular clues as to how the heart can compensate metabolically and maintain viability for weeks after mitochondria are absent or unfunctional.

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