Mitochondrial dynamics in heart disease

Abstract

Mitochondrial fission and fusion have been observed, and their importance revealed, in almost every tissue and cell type except adult cardiac myocytes. As each human heart is uniquely dependent upon mitochondria to generate massive amounts of ATP that fuel its approximately 38 million contractions per year, it seems odd that cardiac myocytes are the sole exception to the general rule that mitochondrial dynamism is important to function. Here, I briefly review the mechanisms for mitochondrial fusion and fission and examine current data that dispel the previous notion that mitochondrial fusion is dispensable in the heart. Rare and generally overlooked examples of cardiomyopathies linked either to naturally-occurring mutations or to experimentally-induced mutagenesis of mitochondrial fusion/fission genes are described. New findings from genetically targeted Drosophila and mouse models wherein mitochondrial fusion deficiency has specifically been induced in cardiac myocytes are discussed. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology.

Figure 1. Subcellular arrangement of mitochondria in normal adult cardiomyocytes

Transmission electron micrograph of normal 8 week old mouse myocardium. Note lanes of interfibrillar mitochondria running between individual myofibrils and cluster of mitochondria surrounding nucleus (bisected on right margin). The “sardines in a can” arrangement appears to enforce inter-organelle contact and does not permit meaningful intra-cellular mitochondrial transport.

Figure 2. Optical coherence tomography of normal and mitochondrial fusion-defective Drosophila hearts

A. Representative images of a fruit fly heart tube in cross section (left), one isolated mouse cardiac myocyte (middle) and human epidermal sweat glands (right), each acquired under the same conditions. Scale bar is 200 microns. B. Line-scan images of representative Drosophila heart tube contractions, showing chamber diameter as a function of time. Top is control fly and bottom is MARF RNAi fly. End-systolic and end-diastolic dimensions (ESD and EDD) are indicated for one cardiac cycle each to the right.

Figure 3. Mitochondrial fragmentation in mouse hearts with defective mitochondrial fusion

Transmission electron micrograph of Mfn1/Mfn2 double null mouse myocardium 3 weeks after conditional gene ablation with tamoxifen. White arrow indicates a normal appearing mitochondrion. Black arrows point to representative small and translucent “fragmented” mitochondria.