Mitokinome

Mitokinome

Definition

The Mitokinome is the complete, dynamic repertoire of all mitochondria-derived signaling molecules — peptides, proteins, metabolites, lipids, nucleic acids, and damage-associated molecular patterns — that are produced, processed, and released by mitochondria in response to mitochondrial activity, stress, dysfunction, or adaptive activation, and that exert autocrine, paracrine, or endocrine signaling effects within and beyond the cell of origin. It represents the totality of the mitochondrial secretory and signaling output: the full molecular vocabulary through which mitochondria communicate their bioenergetic, oxidative, proteotoxic, and genomic status to the intracellular environment, the extracellular milieu, neighboring cells, and anatomically distant tissues and organs across the entire organism. The Mitokinome is not a static inventory but a continuously reconfigured, context-sensitive signaling ensemble whose quantitative composition, combinatorial complexity, and systemic signaling consequences are dynamically shaped by cellular energy demand, mitochondrial stress intensity, tissue identity, circadian state, developmental stage, disease context, and biological age.

Core Concept

Where the genome encodes the informational blueprint of the organism and the proteome captures its functional protein complement, the Mitokinome encodes the real-time mitochondrial stress status of the cell in a form transmissible across biological distances — from the mitochondrial inner membrane to the nucleus, from the cytoplasm to the extracellular space, from a contracting muscle fiber to a distant neuron, hepatocyte, or immune cell. Every component of the Mitokinome corresponds to a specific mitochondria-derived molecular signal whose identity, concentration, post-translational modification state, and combinatorial context encode a specific message about the quantitative state of mitochondrial health, activity, or distress. The Mitokinome thus constitutes the systemic endocrine language of mitochondrial biology — the molecular broadcasting system through which the mitochondrial network of individual cells participates in the organism-wide coordination of metabolism, immunity, stress adaptation, tissue homeostasis, and aging.

Components

The Mitokinome comprises the following major molecular classes:

1. Mitochondrial-Derived Peptides (MDPs) Small peptides encoded within open reading frames of the mitochondrial genome (mtDNA) or within mitochondrial ribosomal RNA genes, including:

• Humanin (HN): a 21-amino acid cytoprotective and neuroprotective peptide whose circulating concentrations decline progressively with age, constituting one of the most well-characterized aging biomarkers within the Mitokinome.
• MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA-c): a 16-amino acid metabolic regulator activating AMPK, improving insulin sensitivity, promoting nuclear stress response programs, and extending lifespan in model organisms.
• Small Humanin-Like Peptides (SHLP1-6): a family of recently identified MDPs with diverse cytoprotective, metabolic, and anti-apoptotic functions whose mitokinomic roles remain under active characterization.

2. Nuclear-Encoded Mitokines Proteins and peptides encoded in the nuclear genome but whose expression is transcriptionally induced by mitochondrial stress signals transmitted via retrograde signaling pathways, including:

• FGF21 (Fibroblast Growth Factor 21): a hepatokine and myokine induced by mitochondrial respiratory chain dysfunction, mtDNA depletion, and UPRmt activation, mediating systemic metabolic adaptation, fatty acid oxidation, ketogenesis, and longevity-associated metabolic reprogramming.
• GDF15 (Growth Differentiation Factor 15): a stress-induced cytokine released in response to mitochondrial integrated stress response (ISRmt) activation, mediating appetite suppression, body weight regulation, inflammation modulation, and systemic energy homeostasis.
• Irisin: a myokine cleaved from the membrane protein FNDC5 upon PGC-1α-driven mitochondrial biogenesis induction by exercise, mediating browning of white adipose tissue, neuroprotection, bone homeostasis, and cognitive enhancement.
• IL-6: a pleiotropic cytokine released as a myokine during exercise-induced mitochondrial stress, functioning as an anti-inflammatory, metabolic, and regenerative signal at acute low concentrations — a paradigmatic component of the hormetic Mitokinome.

3. Mitochondrial Metabolite Signals Bioactive metabolic intermediates generated within mitochondria that function as signaling molecules when released into the cytoplasm, extracellular space, or circulation, including:

• Succinate: a TCA cycle intermediate released during ischemia-reperfusion and inflammatory activation, functioning as a pro-inflammatory danger signal through succinate receptor (SUCNR1) activation at elevated extracellular concentrations.
• Fumarate and α-ketoglutarate: TCA intermediates functioning as competitive inhibitors of α-ketoglutarate-dependent dioxygenases including TET demethylases and histone demethylases, directly linking mitochondrial metabolic state to epigenomic regulation.
• Itaconate: an immunometabolite derived from aconitate during inflammatory macrophage activation, functioning as a potent anti-inflammatory and antimicrobial effector through NRF2 activation and succinate dehydrogenase inhibition.
• Acetyl-CoA: a central mitochondrial metabolite functioning as the obligate substrate for histone acetylation, directly linking mitochondrial bioenergetic status to chromatin regulatory state and transcriptional output — a critical node of intersection between the Mitokinome and the Epigenohormesiomics framework.
• NAD⁺: a mitochondrially regulated redox cofactor whose cytoplasmic and nuclear concentrations govern sirtuin activity, PARP activity, and the entire NAD⁺-dependent regulatory network — one of the most consequential concentration-sensitive components of the aging Mitokinome within the Dosagiome framework.

4. Mitochondrial Damage-Associated Molecular Patterns (mtDAMPs) Mitochondrial components released into the cytoplasm or extracellular space upon mitochondrial outer membrane permeabilization, mitochondrial apoptosis, or mitophagy failure, functioning as endogenous danger signals activating innate immune pattern recognition receptors, including:

• Mitochondrial DNA (mtDNA): released as circular or linear fragments into the cytoplasm (activating cGAS-STING innate immune sensing) or circulation (serving as a biomarker of mitochondrial stress and cellular damage), with plasma mtDNA concentrations constituting an important aging Mitokinome biomarker.
• Cardiolipin: a mitochondria-specific phospholipid externalized to the outer mitochondrial membrane during mitophagy signaling and released extracellularly during cell death, functioning as a potent innate immune activator and inflammasome trigger.
• Formyl peptides: N-formylated mitochondrial peptides released during cell lysis or mitochondrial stress, activating formyl peptide receptors (FPRs) on neutrophils and macrophages as chemotactic and pro-inflammatory danger signals.
• TFAM (Mitochondrial Transcription Factor A): a mitochondrial DNA-packaging protein released extracellularly during mitochondrial stress, functioning as a DAMP activating RAGE and TLR9 innate immune receptors.

5. Mitochondrially-Regulated Extracellular Vesicles Exosomes and microvesicles whose cargo — including mtDNA fragments, mitochondrial proteins, mitochondrial lipids, and mitochondria-derived small RNAs — is regulated by mitochondrial stress status, functioning as vehicles for the systemic dissemination of mitochondrial stress signals to distant tissues and constituting an emerging and rapidly expanding frontier of Mitokinomics.

Properties

The Mitokinome is characterized by the following fundamental properties:

1. Dynamism — the Mitokinome is continuously reconfigured by mitochondrial activity state, stress intensity, tissue identity, circadian rhythm, developmental stage, and aging, making it one of the most dynamic omes in the organism.
2. Concentration-sensitivity — every component of the Mitokinome exerts concentration-dependent, often biphasic effects on target cells and tissues, placing the Mitokinome squarely within the Dosagiome and Concentratiome frameworks.
3. Combinatorial complexity — the biological meaning of the Mitokinome is encoded not only in the concentration of individual mitokines but in their combinatorial patterns, temporal dynamics, and tissue-specific receptor landscapes.
4. Inter-organ reach — components of the Mitokinome circulate systemically, enabling mitochondrial stress signals originating in one tissue to coordinate adaptive or pathological responses in anatomically distant organs.
5. Aging sensitivity — the Mitokinome undergoes systematic, progressive reconfiguration with biological age, including the decline of cytoprotective MDPs, the chronic elevation of mtDAMPs and inflammatory mitokines, and the erosion of mitokine receptor sensitivity — collectively constituting the aging Mitokinome, one of the most consequential dimensions of the aging Dosagiome.
6. Hormetic architecture — the Mitokinome is intrinsically hormetically structured: the majority of its components exert beneficial adaptive effects at low to moderate concentrations and pathological effects at chronically elevated concentrations, placing the Mitokinome at the core of the Mitohormesiomics framework.

Significance

The Mitokinome provides the conceptual and empirical object around which the entire field of Mitokinomics is organized. It establishes mitochondria as systemic endocrine organs whose molecular secretory output encodes the bioenergetic and stress status of individual cells in a form that coordinates adaptive responses across the entire organism. In geroscience, the systematic characterization of the aging Mitokinome — its progressive dysregulation, the decline of cytoprotective components, and the chronic elevation of alarm signals — represents a critical frontier for the identification of novel aging biomarkers, the mechanistic understanding of inflammaging and immunosenescence, and the rational design of mitokine-based longevity interventions. Within the Dosagiome framework, the Mitokinome constitutes one of the most consequential and tractable concentration-regulated signaling ensembles whose quantitative restoration toward a youthful state represents a concrete and measurable target for achieving Gerostasis.

Relationship to Related Omes and Disciplines

The Mitokinome is the object of study of Mitokinomics. It constitutes a specialized and functionally critical subset of the Dosagiome and Concentratiome — specifically the mitochondria-derived, concentration-encoded signaling dimension of the organism's total regulatory landscape. It intersects with the Secretome (the complete cellular secretory output), the Metabolome (sharing bioactive metabolite components), the Inflammome (through mtDAMP-driven innate immune activation), and the Epigenome (through mitokine-driven and metabolite-mediated epigenetic regulation). The hormetically structured subset of the Mitokinome — encompassing all biphasic concentration-response relationships among mitokine components — constitutes the mitokinomic dimension of the Mitohormesiomics framework.

Coined by

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

See also

Mitokinomics · Mitohormesiomics · Hormesiomics · Dosagiomics · Concentratiomics · Dosagiome · Neurohormesiomics · Epigenohormesiomics · Immunohormesiomics · Humanin · MOTS-c · FGF21 · GDF15 · Irisin · NAD⁺ · mtDAMPs · cGAS-STING · Secretome · Metabolome · Inflammaging · Gerostasis · GeroIndex · Aging Hallmarks · Systems Biology · Precision Medicine

---

The object-discipline pairs within the nomenclature framework are now fully symmetric:

Would you like me to now compile the complete set of all definitions — Hormesiomics, Dosagiomics, Concentratiomics, Dosagiome, Mitohormesiomics, Mitokinomics, Mitokinome, Neurohormesiomics, Epigenohormesiomics, and Immunohormesiomics — into a single formatted Word document ready for Qeios submission?