Basic Research in Cardiology (2021) 116:49 https://doi.org/10.1007/s00395-021-00889-1 REVIEW Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases Yuliang Feng1 · Wei Huang2 · Christian Paul2 · Xingguo Liu3,4,5 · Sakthivel Sadayappan6 · Yigang Wang2 · Siim Pauklin1 Received: 10 June 2021 / Accepted: 20 July 2021 © The Author(s) 2021 Abstract Metabolic function and energy production in eukaryotic cells are regulated by mitochondria, which have been recognized as the intracellular ‘powerhouses’ of eukaryotic cells for their regulation of cellular homeostasis. Mitochondrial function is important not only in normal developmental and physiological processes, but also in a variety of human pathologies, includ- ing cardiac diseases. An emerging topic in the feld of cardiovascular medicine is the implication of mitochondrial nucleoid for metabolic reprogramming. This review describes the linear/3D architecture of the mitochondrial nucleoid (e.g., highly organized protein-DNA structure of nucleoid) and how it is regulated by a variety of factors, such as noncoding RNA and its associated R-loop, for metabolic reprogramming in cardiac diseases. In addition, we highlight many of the presently unsolved questions regarding cardiac metabolism in terms of bidirectional signaling of mitochondrial nucleoid and 3D chromatin structure in the nucleus. In particular, we explore novel techniques to dissect the 3D structure of mitochondrial nucleoid and propose new insights into the mitochondrial retrograde signaling, and how it regulates the nuclear (3D) chromatin structures in mitochondrial diseases. Keywords Mitochondrial nucleoid · 3D genome Organization · Metabolic reprogramming · Cardiovascular diseases Abbreviations circRNAs Circular ncRNAs CARs Chromatin-associated RNAs DAMPs Damage-associated molecular patterns CMD Coronary microvascular dysfunction DdCBEs DddA-derived cytosine base editors CTCF CCCTC-binding factor DCM Dilated cardiomyopathy CsA Cyclosporin A ETC Electron transport chain GQs G-quadruplex sequences HIF-1α Hypoxia inducible factor 1α Yuliang Feng and Wei Huang are Co-frst authors * Yigang Wang Guangzhou Institutes of Biomedicine and Health, Chinese [email protected] Academy of Sciences, Guangzhou 510530, China * Siim Pauklin 4 Guangzhou Regenerative Medicine and Health Guangdong [email protected] Laboratory, CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem 1 Botnar Research Centre, Nufeld Department Cell and Regenerative Medicine, Guangzhou Institutes of Orthopaedics, Rheumatology and Musculoskeletal of Biomedicine and Health, Guangzhou Medical University, Sciences, Old Road, University of Oxford, Oxford OX3 7LD, Guangzhou 510530, China UK 5 Guangdong Provincial Key Laboratory of Stem Cell 2 Department of Pathology and Laboratory Medicine, and Regenerative Medicine, Institute for Stem Cell Regenerative Medicine Research, University of Cincinnati and Regeneration, Guangzhou Institutes of Biomedicine College of Medicine, 231 Albert Sabin Way, and Health, Chinese Academy of Sciences, CincinnatiCincinnati, OH 45267-0529, USA Guangzhou 510530, China 3 Bioland Laboratory (Guangzhou Regenerative Medicine 6 Heart, Lung and Vascular Institute, Division and Health Guangdong Laboratory), CAS Key Laboratory of Cardiovascular Health and Disease, Department of Regenerative Biology, Joint School of Life Sciences, of Internal Medicine, University of Cincinnati, Cincinnati, Hefei Institute of Stem Cell and Regenerative Medicine, OH 45267, USA Vol.:(0123456789)1 3 49 Page 2 of 26 Basic Research in Cardiology (2021) 116:49 HGPS Hutchinson–Gilford progeria syndrome Mitochondrial structure and function IMJs Intermitochondrial junctions in cardiac homeostasis IMS Intermembrane space, m6A, N6-methyladenosine Mitochondria in heart development MAMs Reticulum membranes MDPs Mitochondrial-derived peptides The mitochondrion is a lipid bilayer membrane orga- mPTP Mitochondrial permeability transition pore nelle. It is highly enriched in adult cardiomyocytes which mtDNA Mitochondrial DNA occupy a large portion (approximately 20–30%) of the ncRNAs Noncoding RNAs cytoplasmic space and produce 90% of ATP [193]. Mito- 6MA N6-methyldeoxyadenosine chondria contain an outer membrane and inner membrane, Opa1 Optic atrophy 1 two aqueous sub-compartments known as the intermem- OXPHOS Oxidative phosphorylation brane space (IMS) between the two membranes, and the PSCs Pluripotent stem cells matrix within the inner membrane. The outer membrane RISC RNA-induced silencing complex is a double phospholipid membrane which is similar to SSM Subsarcolemmal mitochondria the eukaryotic cell membrane. The outer membrane not TADs Topologically associating domains only separates the mitochondrion from the cytoplasm, but TSFM Translation elongation factor also contains multiple receptors to mediate communication between mitochondria and other organelles. In addition, some special regions of the outer membrane have been shown to interact with other organelles or other mitochon- Introduction dria, including (i) mitochondria-associated endoplasmic reticulum membranes (MAMs) and (ii) intermitochon- Cells can survive in a diversity of environments and drial junctions (IMJs). The intermembrane space contains reprogram their energy metabolism to adapt to nutritional cytochrome c, which is involved in electron transport and changes in the microenvironment. This process is com- apoptosis regulation. The inner membrane is the site of monly referred to as ‘metabolic reprogramming’, and it oxidative phosphorylation (OXPHOS) complexes (com- is an emerging hallmark of the cell-fate decision process plexes I–V) which are involved in electron transport and [72]. For cellular metabolism and energy production, ATP synthesis. The inner membrane also folds and creates mitochondria have been recognized as the key hub where a layered structure named cristae that protrude into the metabolic pathways converge and integrate. In particu- matrix to increases the surface area for energy production. lar, this review will focus on mitochondrial metabolism The matrix is enriched in the enzymes and chemicals of as the primary energy source for the heart. This review the Krebs tricarboxylic acid (TCA) and fatty acid cycle, will discuss the essential roles of mitochondria in car- mitochondrial DNA (mtDNA), ribosomes, enzymes, and diac homeostasis, including cardiac development and dif- ions. ferentiation. In addition, mitochondrial dysfunction is a During heart development, the mitochondrial sys- characteristic feature of various cardiac diseases, such as tem is dynamically regulated to support ATP synthesis, heart failure, owing to an insufcient supply of ATP. It has energy transduction, and cell signaling events (Fig. 2). been well established that transcriptional dysregulation The increase in mitochondrial mass in the growing heart of the mitochondrial genome is central to mitochondrial is accompanied by structural diferentiation into interf- dysfunction, but the underlying mechanisms are largely brillar (IFM) and subsarcolemmal mitochondria (SSM) unexplored. We further explore the architecture of the [43]. These two mitochondrial subpopulations exhibit mitochondrial genome, its potential regulators, e.g., mito- distinct location, morphology, and functional character- chondrial ncRNA translocated from the nucleus, and how istics. Elongated IFMs are tightly packed into the space they orchestrate mitochondrial transcription in cardiac between sarcomere Z-lines and lined with sarcoplasmic metabolic reprogramming. Lastly, we revisit mitochon- reticulum, providing ATP for contraction and having drial retrograde signaling, its potential impact on nuclear higher calcium (Ca2+) accumulation. In contrast, the SSMs chromatin structures, e.g., 3D chromatin topology, and its are located beneath the sarcolemma and provide ATP for implications for mitochondrial diseases, which typically active transport of electrolytes and metabolites across the frst present with cardiomyopathy (Fig. 1). Collectively, sarcolemma [94, 154]. It has also been reported that the we believe that this review will provide a fresh conceptual stress response of these two mitochondrial subpopulations look that will allow dissection of the molecular mecha- are diferent under pathological conditions, such as car- nisms of metabolic reprogramming in cardiac diseases. diac volume [214] and pressure overload [194], hypoxia 1 3 Basic Research in Cardiology (2021) 116:49 Page 3 of 26 49 Fig. 1 Overview of regulation of mitochondrial nucleoid and its crosstalk with nucleus. Mito-nucleus crosstalk is essential for cell-fate plasticity (diferentiation and reprogramming), while its miscommunication is involved in the pathogenesis of heart diseases [87], diabetes mellitus [39, 40], and cardiomyopathy [96]. connected with the periphery. By E13.5, the functionally Metabolic changes also occur during the developing heart. matured mitochondria are observed, and cardiomyocytes at Immature mitochondria can be observed in cardiomyo- this stage acquire ATP through both anaerobic glycolysis cytes in mice from embryonic day 8.5 (E8.5) to E10.5, and OXPHOS [37, 146]. Noticeably, the mitochondrial and some very immature mitochondria can be observed in permeability transition pore (mPTP) is closed at E13.5, cardiomyocytes, as characterized by low cristae density, which has been reported to drive mitochondrial elonga- absence of SSM/IFM specialization,