Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks

Abstract

Cardiovascular homeostasis is increasingly understood not as the output of isolated pathways, but as an emergent and history-dependent property of interactions across biological scales. Cutting-edge technologies have revealed coupling between transcription and metabolism, signaling within molecular microdomains, organelle networks, communication between cardiomyocytes and non-myocytes, neurovascular regulation, and interorgan interactions. This special issue brings together five perspectives that examine how such interactions preserve physiological function and, under stress, redirect the cardiovascular system toward adaptation or disease. As a representative multiscale example, this Editorial highlights hierarchical mitochondrial quality control. Biogenesis, fusion–fission dynamics, proteostasis, mitochondria-derived vesicles, organelle contacts, and mitophagy form a graded defense network that matches the response to the burden and location of damage. The same network connects mitochondrial dysfunction to innate immunity and tissue remodeling. Defining directionality, spatial context, temporal order, and flux within these interactions will be essential for converting descriptive interaction maps into causal physiology and selective therapies.

Homeostasis as a relational property

Physiology has long explained cardiovascular homeostasis through interactions: excitation–contraction coupling in cardiomyocytes, neurohumoral control of the circulation, and reciprocal signaling between the heart and peripheral organs. What is changing is the resolution at which these relationships can now be observed. Trans-omics approaches connect transcriptional programs to protein activity and metabolism, while single-cell and spatial methods resolve heterogeneous cell states and infer communication within intact tissues. The adult human heart itself contains diverse cardiomyocyte, vascular, stromal, and immune populations whose spatially organized interactions cannot be reduced to a cardiomyocyte-only model [1]. These advances invite a broader definition of homeostasis. It is not merely the maintenance of a fixed set point. It is the capacity of a network to preserve function while continuously exchanging information, substrates, force, and damaged material. The same interaction can be stabilized in one context and transformative in another. A microdomain may sharpen a physiological signal, yet chronic reinforcement can create a maladaptive signaling niche. An immune–stromal circuit can support repair, yet persistent activation can promote fibrosis. Autonomic compensation can sustain perfusion acutely yet accelerate remodeling when prolonged. Thus, the central question is no longer only which molecule or cell changes, but which interaction changes, where, when, and in which direction.

The contributions assembled in this special issue approach this question from complementary scales. One examines myeloid-driven remodeling as a transition from single-cell states to multicellular circuits in the diseased heart. A second focuses on the functional linkage between mRNA transcription and decay during cardiac stress, emphasizing that gene expression is governed by coordinated production and removal rather than transcription alone. A third explores autonomic dysfunction in pulmonary hypertension and the reciprocal relationship between pulmonary circulation and neural regulation. A fourth considers how the tissue environment surrounding the heart reshapes cardiac function. A fifth revisits phosphodiesterase-controlled microdomains, showing how the spatial organization of cyclic-nucleotide signaling contributes to both homeostasis and remodeling. Together, these articles span molecular coupling, subcellular compartmentation, cell–cell communication, tissue ecology, and organ-level neural control. Their common message is that biological scale should not be treated as a set of disconnected layers. Molecular events acquire meaning within organelles and microdomains; cell states are stabilized or redirected by neighboring cells; and tissue-level outputs feed back to neural, metabolic, and immune systems. The phrase “maintaining and transfiguring” is therefore deliberate: interaction networks both defend the current state and define the routes by which a new state emerges.

Hierarchical mitochondrial quality control: A multiscale example

Mitochondrial quality control illustrates this principle particularly well in the heart, where energy demand is high and mitochondrial mass cannot be indiscriminately discarded. The system is organized as a graded defense network (Fig. 1). At the first level, PGC-1α–NRF1/2–TFAM-dependent biogenesis replenishes mitochondrial components, while fusion mediated by MFN1/2 and OPA1 mixes contents and supports complementation. At a more local level, chaperones and matrix or inner-membrane proteases—including LONP1, CLPP, and OMA1—repair or remove damaged proteins. Mitochondria-derived vesicles selectively export oxidized cargo to lysosomes or peroxisomes, providing a resource-sparing alternative to organelle-wide elimination; PINK1 and Parkin participate in at least one such vesicular pathway [2]. When damage becomes spatially confined but no longer locally reparable, fission separates dysfunctional regions from the network. DRP1 is recruited to outer-membrane adaptors such as MFF, FIS1, and MiD49/51, while endoplasmic reticulum contact and actin assembly help define division sites [3]. Mitochondria–lysosome contacts provide an additional spatial checkpoint through RAB7-dependent control of fission [4]. If membrane potential and functional integrity cannot be restored, whole-organelle mitophagy is mobilized through PINK1–Parkin, receptor-mediated pathways involving BNIP3, NIX, or FUNDC1, and alternative pathways involving RAB9, ULK1, and dynamin-related protein 1 (DRP1). The guiding logic is to use the least costly effective response: preserve mitochondrial mass whenever possible and remove only the damaged unit when necessary.

Fig. 1.

Hierarchical mitochondrial quality control across biological scales. Cardiovascular homeostasis emerges from coordinated molecular, organelle, cellular, and tissue-level interactions. Damage severity determines the least costly effective response. Repair and selective export preserve mitochondrial mass, whereas irreversible damage triggers mitophagy. When quality control fails, mtDNA and cardiolipin are released, thereby activating innate immune signaling and promoting inflammation, fibrosis, and cardiac remodeling.

This hierarchy also cautions against binary interpretations of mitochondrial dynamics. Fragmentation often accompanies cardiac stress, but fission is required to segregate damage and enable quality-selective removal. Indeed, combined disruption of mitochondrial fusion and fission accelerates mitochondrial senescence in the heart [5]. Likewise, inhibition of DRP1 without regard to context may suppress both pathological hyperfission and protective quality control. Interaction-selective mechanisms may provide greater precision. Hypoxic recruitment of DRP1 by filamin A promotes mitochondrial hyperfission and myocardial senescence [6], whereas the redox and polysulfidation state of DRP1 can alter its function and influence cardiac vulnerability [7]. These observations shift the therapeutic target from “fission” to the molecular interface, modification, location, and timing that confer pathological activity. Under hypoxic stress, we found that the actin-binding protein filamin A acts as a guanine nucleotide exchange factor for DRP1 and recruits it to mitochondrial fission sites. Formation of the DRP1–filamin A complex promoted mitochondrial hyperfission, reactive oxygen species production, and premature myocardial senescence after myocardial infarction; pharmacological interference with this interaction suppressed these maladaptive responses [6]. We subsequently showed that exposure to a low, non-neurotoxic dose of methylmercury depolysulfidates a redox-sensitive cysteine residue of DRP1 (Cys624 in rat DRP1, corresponding to Cys644 in human DRP1). This loss of the bulky polysulfide modification facilitated filamin-dependent DRP1 activation and mitochondrial hyperfission, thereby markedly increasing cardiac vulnerability to pressure overload. A reactive polysulfide donor reversed DRP1 depolysulfidation, mitochondrial hyperfission, and susceptibility to mechanical stress [7]. These findings identify a mechanistic link by which an environmental electrophile can erode an endogenous sulfur-dependent safeguard and lower cardiac robustness.

More recently, we extended this concept to ischemic heart failure and demonstrated that the chemical state of Cys644 functions as a stress-responsive molecular switch. Hypoxic and pseudohypoxic stress promoted supersulfide catabolism and DRP1 depolysulfidation, whereas oxidized glutathione (GSSG), but not reduced glutathione (GSH), preferentially induced S-glutathionylation of polysulfidated Cys644. This polysulfur-based molecular bulking prevented DRP1–filamin A complex formation, mitochondrial hyperfission, and myocardial senescence. Consistently, GSSG improved mitochondrial bioenergetics and cardiac function after myocardial infarction in mice, and knock-in analysis established the importance of Cys644 for both ischemic tolerance and the protective effect of GSSG [8]. Together, the three studies show that pathological fission is specified not simply by the amount of DRP1, but by its interaction partner and context-dependent sulfur chemistry. They therefore shift the therapeutic target from ‘fission’ as a whole to the molecular interface, modification, location, and timing that confer pathological activity.

The hierarchy is dynamic and disease-specific. Mitophagy flux can be blunted during metabolic stress in models of heart failure with preserved ejection fraction [9], whereas PINK1-mediated mitophagy can restrain pressure-overload remodeling by limiting mitochondrial DNA release and cGAS–STING activation [10]. Thus, abundance measurements such as Parkin or LC3-II alone are insufficient. Flux reporters, lysosomal competence, mitochondrial mass, metabolic substrate use, and disease stage must be evaluated together. Quality control is not an isolated housekeeping pathway; it is an interaction network that connects organelle morphology, metabolism, degradation, innate immunity, and tissue remodeling.

Importantly, mitochondrial quality control can also be distributed among cells (Fig. 2). Cardiomyocytes can transfer damaged mitochondria or mitochondrial components through extracellular vesicles, tunneling nanotubes, or related routes to macrophages and stromal cells, extending disposal beyond cell-autonomous mitophagy; cardiac-resident macrophages support mitochondrial homeostasis by clearing cardiomyocyte-derived material [11]. Conversely, transfer of functional mitochondria from stromal, fibroblast, or vascular donor cells may enhance respiration and survival in stressed recipient cells, consistent with foundational demonstrations of intercellular mitochondrial rescue [12]. Cargo quality therefore determines whether transfer functions as disposal, rescue, or inflammatory propagation: vesicles enriched in oxidized mitochondrial DNA or dysfunctional mitochondria may activate innate immune pathways in recipient cells. Intercellular quality control is thus a tissue-level extension of the hierarchy, but its direction, donor and recipient identities, persistence, and cargo fate must be resolved in vivo.

Fig. 2.

Intercellular mitochondrial quality control enables disposal or rescue, but damaged cargo may propagate inflammation.

From interaction maps to causal physiology

High-dimensional datasets are exceptionally powerful for discovering candidate relationships, but co-variation is not yet interaction and interaction is not yet mechanism. The next phase of cardiovascular physiology should test at least five properties. First, directionality: which component is the sender, and which is the receiver? Second, spatial context: does the event occur in a membrane microdomain, an organelle contact, a defined tissue niche, or the systemic circulation? Third, temporal order: is the interaction an initiating event, compensation, or consequence? Fourth, flux: how rapidly do signals, metabolites, organelles, or damaged cargo move through the system? Fifth, state dependence: how do sex, age, disease stage, metabolic substrate, and prior stress alter the sign or strength of the relationship? Answering these questions will require combinations of spatially resolved omics, lineage and cargo tracing, live-cell and in vivo reporters, controlled perturbations, and classical physiological measurements. Particularly informative experiments will perturb an interface while preserving the individual components; for example, disrupting a pathological protein complex without abolishing the entire process, or altering a cell–cell signal in a defined time window. Such strategies can reveal whether an interaction is necessary, sufficient, compensatory, or merely correlated.

Conclusions and Perspective

The cardiovascular system survives because its parts do not act alone. Molecules are organized into microdomains, organelles negotiate damage and resources, cells exchange signals and material, and neural and circulatory systems continually reshape one another. These interactions maintain homeostasis, but they also provide routes through which chronic stress is encoded as remodeling and disease. The articles in this special issue offer distinct entry points into this shared problem and, collectively, encourage a physiology of relationships: one that integrates scales without losing mechanism.

Hierarchical mitochondrial quality control provides one model for this approach. Its protective effect arises not from a single pathway, but from coordination among repair, selective export, dynamics, organelle contacts, and elimination. Therapeutic opportunity may therefore lie in restoring the architecture and timing of interactions rather than maximizing or suppressing one node. By connecting new analytical technologies with causal physiological reasoning, we hope this special issue will stimulate “learning from the old to create the new” and open new paths toward understanding - and ultimately redirecting - cardiovascular remodeling.

CRediT authorship contribution statement

Motohiro Nishida: Writing – review & editing, Writing – original draft, Visualization, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.