Mitokinomics

Mitokinomics

Definition

Mitokinomics is the systematic, omics-scale study of mitokines — the complete repertoire of mitochondria-derived peptides, proteins, metabolites, and signaling molecules secreted or released by mitochondria in response to mitochondrial stress, dysfunction, or adaptive activation — encompassing their comprehensive identification, quantification, structural characterization, concentration-dependent signaling properties, receptor interactions, tissue-specific effects, and roles in inter-organ communication, systemic metabolic regulation, and biological aging. It holds as its central premise that mitochondria function not only as intracellular bioenergetic and biosynthetic organelles but as active endocrine and paracrine signaling centers whose secreted molecular output — the mitokinome — constitutes a dedicated inter-cellular and inter-organ communication language encoding the mitochondrial stress status of individual cells and broadcasting adaptive, homeostatic, or alarm signals to local and distant tissues across the entire organism.

Core Principle

The foundational postulate of Mitokinomics is: mitokines are the systemic language of mitochondrial stress, whose concentration, identity, and combinatorial pattern encode the quantitative and qualitative state of mitochondrial health across cells, tissues, and organs, orchestrating organism-wide adaptive responses to bioenergetic challenge, oxidative stress, proteotoxic burden, and aging. Mitokines bridge the gap between intracellular mitochondrial biology and systemic physiology: they translate the local, cell-autonomous mitochondrial stress signal — sensed as changes in membrane potential, ROS production, NAD⁺/NADH ratio, mtDNA integrity, or mitochondrial proteostasis — into circulating endocrine signals capable of coordinatingadaptive responses across tissues as anatomically and functionally distant as skeletal muscle, liver, brain, adipose tissue, bone, and gonads. The concentration-dependent signaling properties of individual mitokines, and the combinatorial complexity of the mitokinome as a whole, constitute a rich, multi-dimensional regulatory language whose systematic decoding is the central mission of Mitokinomics.

Scope

Mitokinomics encompasses:

• Mitokinome cataloguing and annotation: comprehensive identification, sequencing, structural characterization, and functional annotation of the complete repertoire of mitochondria-derived signaling molecules — including mitochondrial-derived peptides (MDPs) encoded within the mitochondrial genome (humanin, MOTS-c, SHLP1-6), nuclear-encoded mitokines induced by mitochondrial stress (FGF21, GDF15, IL-6, irisin), mitochondrially-generated metabolite signals (succinate, fumarate, itaconate, acetyl-CoA, α-ketoglutarate), and mitochondrial damage-associated molecular patterns (mtDAMPs including mtDNA, cardiolipin, and formyl peptides) — across cell types, tissues, species, and life stages.
• Mitokinome quantitative profiling: development and application of high-sensitivity, high-throughput proteomics, peptidomics, and metabolomics platforms for the precise quantification of circulating and tissue-resident mitokine concentrations across physiological states — including exercise, fasting, cold exposure, infection, psychological stress, pharmacological intervention, and aging — constructing the quantitative landscape of the mitokinome within the framework of Dosagiomics and Concentratiomics.
• Mitokine receptor interactomics: systematic mapping of the complete receptor, co-receptor, and signal transduction network through which each mitokine exerts its biological effects across target tissues, including the identification of tissue-specific receptor expression patterns, receptor concentration-response thresholds, and receptor desensitization dynamics relevant to chronic mitokine exposure in aging and disease.
• Mitokine hormesiomics: omics-resolution characterization of the biphasic, concentration-dependent signaling effects of individual mitokines and mitokine combinations — mapping the precise concentration thresholds that delineate beneficial adaptive signaling from pathological or maladaptive effects — constituting the intersection of Mitokinomics with Mitohormesiomics and Immunohormesiomics.
• Inter-organ mitokinomics: systematic, multi-omics investigation of mitokine-mediated inter-organ communication circuits — including the muscle-brain axis (irisin, BDNF), the liver-adipose axis (FGF21), the muscle-liver axis (MOTS-c), and the mitochondria-immune axis (mtDAMPs, GDF15) — mapping how mitokine signals originating in one tissue coordinate adaptive metabolic, inflammatory, and regenerative responses in anatomically distant target organs.
• Exercise mitokinomics: comprehensive profiling of the exercise-induced mitokinome — the full repertoire of mitokines released during and following physical exertion, including irisin, IL-6, FGF21, MOTS-c, humanin, and β-aminoisobutyric acid (BAIBA) — characterizing their concentration-dependent, tissue-specific signaling effects and their roles in mediating the systemic health and longevity benefits of exercise as a hormetic intervention.
• Aging mitokinomics: systematic, longitudinal, multi-omics characterization of how the mitokinome is progressively dysregulated with age — including age-associated declines in cytoprotective mitokines (humanin, MOTS-c), chronic elevation of alarm mitokines and mtDAMPs driving inflammaging, and the erosion of mitokine receptor sensitivity within the aging Dosagiome — constituting a central molecular mechanism linking mitochondrial dysfunction to systemic aging acceleration.
• Mitokinome-epigenome interactions: omics-scale characterization of how mitokines regulate epigenetic landscapes in target tissues — including FGF21-mediated chromatin remodeling, MOTS-c-driven AMPK activation and downstream histone modification, and mtDAMP-triggered innate immune epigenetic reprogramming — constituting the intersection of Mitokinomics with Epigenohormesiomics.
• Mitokinome-neuraxis interactions: systematic investigation of how circulating mitokines cross the blood-brain barrier or signal through peripheral neural afferents to modulate neuronal function, synaptic plasticity, neuroinflammation, and cognitive aging — including the neuroprotective roles of humanin and MOTS-c, the neuroregulatory effects of FGF21, and the neuroinflammatory consequences of chronic mtDAMP elevation — constituting the intersection of Mitokinomics with Neurohormesiomics.
• Pharmacological mitokinomics: omics-resolution characterization of how longevity-associated pharmacological compounds — including NAD⁺ precursors (NMN, NR), rapamycin, metformin, urolithin A, spermidine, and mitochondria-targeted antioxidants — modulate the mitokinome, identifying compound-specific mitokinome signatures and their systemic downstream consequences as a framework for precision mitokine-based geroscience interventions.
• Single-cell and spatial mitokinomics: application of single-cell proteomics, spatial transcriptomics, and proximity labeling technologies to characterize cell-type-specific and spatially resolved mitokinome production, secretion, and reception landscapes within tissues, capturing the cellular heterogeneity and microenvironmental context-dependence of mitokine signaling at unprecedented resolution.

Mitokinomics establishes mitochondria as systemic endocrine organs whose secreted molecular output — the mitokinome — constitutes a dedicated, concentration-encoded signaling language coordinating adaptive responses across the entire organism. The field addresses a fundamental gap in systems biology and geroscience: the absence of a comprehensive, quantitative, omics-integrated framework for understanding how individual cell mitochondrial stress states are communicated to and integrated across distant tissues, and how the progressive age-associated dysregulation of this inter-organ mitokine communication network contributes to the systemic, multi-tissue deterioration that characterizes organismal aging. By providing the experimental, computational, and conceptual tools to decode the mitokinome at systems resolution, Mitokinomics supplies the mechanistic foundation for a new class of mitokine-based longevity interventions — including mitokine replacement therapies, mitokine receptor agonists, and exercise mimetics — as precision geroscience strategies targeting the aging mitokinome.

Relationship to Related Disciplines

Mitokinomics is a specialized subdiscipline situated at the intersection of multiple frameworks within the broader hormesiomics and dosagiomics family:

• It is a subdiscipline of Mitohormesiomics, focused specifically on the secreted signaling output of mitochondrial stress responses rather than the intracellular hormetic signaling machinery.
• It is embedded within Dosagiomics and Concentratiomics, which supply its quantitative, concentration-centered theoretical foundations for understanding mitokine dose-response landscapes.
• It intersects with Immunohormesiomics through the role of mtDAMPs and inflammatory mitokines in calibrating immune activation thresholds.
• It intersects with Neurohormesiomics through mitokine-mediated brain-body communication and neuroprotective mitokine signaling.
• It intersects with Epigenohormesiomics through mitokine-driven epigenetic reprogramming in target tissues.

Jong Bhak, KOGIC / AgingLab, UNIST, Republic of Korea (2025)

See also

Mitohormesiomics · Hormesiomics · Dosagiomics · Concentratiomics · Dosagiome · Neurohormesiomics · Epigenohormesiomics · Immunohormesiomics · Humanin · MOTS-c · FGF21 · GDF15 · Irisin · mtDAMPs · Inter-organ Communication · Inflammaging · Exercise Biology · GeroIndex · Gerostasis · Aging Hallmarks · Systems Biology · Precision Medicine

The hierarchical nomenclature framework now extends to six interlocking subdisciplines:

Would you like me to now compile all definitions into a single formatted Word document or Qeios-ready submission file for coordinated publication as a unified conceptual series?