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Review
. 2023 Sep 29;118(1):39.
doi: 10.1007/s00395-023-01011-3.

Giant mitochondria in cardiomyocytes: cellular architecture in health and disease

Amy Li  1   2   3 , Gerald J Shami  4   5 , Lisa Griffiths  6 , Sean Lal  7 , Helen Irving  8 , Filip Braet  9   10
Affiliations
Review

Giant mitochondria in cardiomyocytes: cellular architecture in health and disease

Amy Li et al. Basic Res Cardiol. .

Abstract

Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.

Keywords: Cardiomyopathy; Giant and megamitochondria; Histopathological marker; Mitochondrial aberrations; Mitochondrion pathophysiology; Muscle disease.

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Conflict of interest statement

On behalf of all authors, the corresponding author states that there is no conflict of interest. The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Morphology of mitochondria in the adult ventricular myocardium based on subcellular organization. A shows highly organized intermyofibrillar (I) mitochondria that are typically cylindrical or oval shaped. Note that nuclear (N) and subsarcolemmal (S) located mitochondria vary greatly in size and shape. B enlargement of intermyofibrillar mitochondria with soft membrane (top pointer) indicative of fusion or fission. Note, the lower pointer indicates clearly defined membranes. C illustrates the ordered arrangement of mitochondria in longitudinal sections on the left and irregularly shaped mitochondria can be observed in obliquely sectioned samples on the right. Scale bars, 5 μm (A); 0.5 μm (B); 2 μm (C). (Fig. 4: Journal of Molecular and Cellular Cardiology by Elsevier [25]. Reproduced and lettering modified with permission of Elsevier in the format Journal/Magazine via Copyright Clearance Center)
Fig. 2
Fig. 2
Transmission electron microscopy micrographs of enlarged mitochondria in rat papillary muscle derived from the left ventricular myocardium. A Longitudinally orientated muscle section shows elongated subsarcolemmal mitochondria and B transverse section showing concentric arrangement of cristae. End magnifications, × 43,000 (A); × 53,000 (B). (Figs. 1 and 24: The Journal of Biophysical and Biochemical Cytology by Rockefeller Institute Press [65]. Reproduced and lettering modified with permission of Rockefeller Institute Press in the format Journal/Magazine via Copyright Clearance Center)
Fig. 3
Fig. 3
Giant mitochondria in canary myocardial tissue. A The size and shape of giant mitochondria varies significantly from B block-like to C rod-like formation. Giant mitochondria contain both retiform (R) and zig-zag (Z) arrangements of cristae. End magnifications, × 27,000 (A); × 60,000 (B); × 23,000 (C). (Figs. 1, 2 and 14: Journal of Cell Biology by Rockefeller Institute Press [62]. Reproduced and lettering modified with permission of Rockefeller Institute Press in the format Journal/Magazine via Copyright Clearance Center)
Fig. 4
Fig. 4
Cultured adult rat ventricular cardiomyocyte (ARVC). A Artificially shadowed confocal microscopy image showing giant cylindrical shaped mitochondria (arrowhead). B Corresponding low magnification transmission electron microscopy image shows the presence of electron-dense inclusions in giant mitochondria. The inclusions can appear as parallel straight lines (arrow) or sheet liked wavy structures (arrowhead). N—nucleus. Periodicity was identified between the parallel straight lines C and within the linear structures (D, arrow). E–F ARVCs gold-labelled with mitochondrial creatine kinase antibody are localized at the site of both forms of the mitochondrial inclusions, but largely absent from mitochondria (m) without inclusions. Scale bars, 15 μm (A); 3 μm (B); 0.45 μm (C & D); 0.5 μm (E & F). (Figs. 1F, 3 and 4: Journal of Cell Biology by The Rockefeller University Press [16]. Reproduced and lettering modified with permission of The Rockefeller University Press in the format Journal/Magazine via Copyright Clearance Center)
Fig. 5
Fig. 5
Electron microscopy observations of mitochondria in the naked mole rat. A shows the presence of a large mitochondrion (arrow) at 5 years of age. Note, the high number of normal-sized mitochondria surrounding the enlarged mitochondrion. B High magnification of the giant mitochondrion from A which illustrates packed wave-like cristae. Note the electron-dense granules scattered throughout the mitochondrial matrix. C At 11-year-old, the large mitochondria show inclusion of highly ordered cristae bundles and a clear reduction in cristae packing. D High magnification of the cristae bundles in C which are arranged in parallel, with a track-like appearance between the double-membraned structures termed membrane junctions or intra-crystal junctions. E Overview of the disrupted mitochondria ultrastructure in 11 year-old naked mole rats with possible sheet-like inclusions. Scale bars, 5 μm (A); 2 μm (B); 1 μm (C); 0.1 μm (D); 2 μm (E). (Figs. 5 and 8: International Journal of Molecular Sciences by MDPI [5]. Reproduced and lettering modified with permission of MDPI in the format Journal/Magazine via MDPI Open Access Policy)
Fig. 6
Fig. 6
Transmission electron micrographs of giant mitochondria in the ventricular myocardium of alcoholic cardiomyopathy. Mice were fed with an alcohol-heavy diet for A 15 or B–D 25 weeks, consisting of 36% of total calories consumed. A Mice fed for 15 weeks with alcohol revealed an increased number and size of mitochondria. The mitochondrial matrix was in general well-preserved. B–D After 25 weeks of alcohol exposure giant mitochondria, some extending the length of 4–5 sarcomeres, were abundantly present with loss of normal mitochondria structure. In brief: B giant mitochondria showing dense cristae (arrow), vacuoles and dense bodies of unknown origin. C Depicting two giant mitochondria that possess varying patterns of ‘crystal’ orientation (arrows). D In some instances, transformation of giant mitochondria into a huge vacuole was observed. Arrow denotes a few remaining cristae remnants. End magnifications, × 8600 (A); × 13,500 (B); × 17,500 (C); × 25,000 (D). (Figs. 2–4: Journal of Molecular and Cellular Cardiology by Elsevier [3]. Reproduced and lettering modified with permission of Elsevier in the format Journal/Magazine via Copyright Clearance Center)
Fig. 7
Fig. 7
Electron microscopy micrographs showing ultrastructural changes of mitochondria in patients with mtDNA mutations. A Ring-shaped mitochondria. B Giant mitochondria with membrane fusion and circular cristae. C Concentric cristae. D Giant ‘organelles’ containing irregularly whorled and undulated cristae. End magnifications, × 5600 (A); × 16,000 (B); × 9600 (C); × 9100 (D). (Fig. 1: American Journal of Pathology by Elsevier [4]. Reproduced and lettering modified with permission of Elsevier’s Open Access Content License policy for the American Society for Investigative Pathology in the format Journal/Magazine and subject to proper acknowledgement of the original source)
Fig. 8
Fig. 8
Fusion and fission events of cultured adult cardiomyocytes. A normal mitochondria. B Fusion of 2–3 mitochondria to form giant mitochondria mediated by Drp1 inhibition. Arrow denotes the area were mitochondria fused. C Mfn1/2 (mitofusins 1 and 2) knockout causes mitochondrial fragmentation (arrow). Note that the mitochondria are rounder and their size decreased. Scale bars, 0.5 μm. (Fig. 3: Frontiers in Cell and Developmental Biology by Frontiers Media SA [36]. Reproduced and lettering modified with permission of Frontiers Media SA in the format Journal/Magazine via Frontiers Copyright Notice Open Policy)
Fig. 9
Fig. 9
Mitochondria morphology from routine diagnostic imaging. A myopathic biopsy was acquired and sent to clinical pathology services for routine histologic and molecular characterization. High-magnification transmission electron micrograph shows several interesting features including enlarged mitochondria, mitochondria with inclusions, abnormal cristae and matrix interspersed between transverse sectioned highly ordered muscle fibers. Of note, in this example, the patient was diagnosed with focal myonecrosis and underpins the importance of examining muscle tissue for mitochondrial aberrations in diagnostic settings. Scale bars, 0.5 μm—end magnification, × 60,000. (Fig. 1: Australian Microscopy and Microanalysis Newsletter [21]. Reproduced and lettering modified with permission of the copyright holder)
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