Mnoptosis

1.1 Mechanism Overview

Mnoptosis is an emerging manganese‑dependent regulated cell death modality triggered by disrupted intracellular Mn²⁺ homeostasis and abnormal Mn²⁺ accumulation. Excessive Mn²⁺ replaces physiological metal cofactors in essential metabolic enzymes through enzymatic mismetallation. Coq7, the key enzyme for mitochondrial coenzyme Q (CoQ) synthesis, acts as the core target. Mn²⁺‑mediated Coq7 dysfunction blocks CoQ biosynthesis, disrupts the mitochondrial electron transport chain (ETC) and oxidative phosphorylation (OXPHOS), leading to impaired mitochondrial respiration, damaged membrane structure and inadequate ATP production, and ultimately induces cell death. Furthermore, Mn²⁺ promotes activation of the cGAS–STING pathway, elicits type I interferon responses and regulates anti‑tumor immunity。

Mnoptosis Mechanism Diagram. Aberrant Mn²⁺ accumulation induces mismetallation of mitochondrial Coq7, blocks CoQ biosynthesis, impairs the electron transport chain and oxidative phosphorylation, triggers mitochondrial structural damage and ATP depletion, and ultimately leads to Mnoptosis. Meanwhile, Mn²⁺ activates the cGAS‑STING pathway to regulate anti‑tumor immunity.

1.2 Target List

Mechanism Module	Target (Gene/Protein)	Full Name	Biological Function	Mechanism in Mn²⁺‑dependent Cell Death	Research Value / Detection Index
Mn²⁺ Homeostasis Regulation	SLC39A8 (ZIP8)	Solute carrier family 39 member 8	Metal ion transporter mediating Mn²⁺ uptake	Promotes intracellular Mn²⁺ accumulation and initiates Mn²⁺ toxicity	Indicator of Mn²⁺ influx
	SLC30A10	Solute carrier family 30 member 10	Mn²⁺ efflux transporter maintaining manganese homeostasis	Reduced Mn²⁺ export increases intracellular Mn²⁺ accumulation	Indicator of Mn²⁺ efflux regulation
COQ7‑dependent Core Execution Mechanism	COQ7	Coenzyme Q7 hydroxylase	Enzyme involved in CoQ biosynthesis	Mn²⁺ induces COQ7 mismetallation, disrupting CoQ metabolism and mitochondrial function	Core execution marker
CoQ Metabolic Pathway Regulation	COQ3	Ubiquinone biosynthesis O‑methyltransferase	Participates in CoQ biosynthetic modification	Dysfunction contributes to impaired CoQ synthesis	Marker of CoQ pathway alteration
	COQ5	Coenzyme Q biosynthesis protein COQ5	Involved in CoQ maturation process	Regulates CoQ biosynthesis efficiency	Indicator of CoQ metabolism
	COQ8A	Coenzyme Q8A protein	Regulates CoQ biosynthesis and mitochondrial function	Alteration affects mitochondrial respiratory activity	CoQ pathway regulatory marker
Mitochondrial Complex I Dysfunction	NDUFS1	NADH dehydrogenase [ubiquinone] Fe‑S protein 1	Component of respiratory Complex I involved in electron transfer	Mn²⁺ stress disrupts Complex I electron transport	Complex I damage marker
	NDUFB8	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8	Structural component of Complex I	Indicates mitochondrial respiratory impairment	Complex I functional marker
Mitochondrial Complex II Dysfunction	SDHA	Succinate dehydrogenase flavoprotein subunit A	Catalyzes succinate oxidation and electron transfer	Mn²⁺ exposure decreases Complex II activity	Complex II function marker
Mitochondrial Complex III Dysfunction	UQCRC2	Ubiquinol‑cytochrome c reductase core protein 2	Component of mitochondrial Complex III	Electron transport inhibition increases mitochondrial oxidative stress	Complex III damage marker
Mitochondrial Complex IV Dysfunction	COX4	Cytochrome c oxidase subunit 4	Regulates cytochrome c oxidase activity and oxygen consumption	Mn²⁺ stress impairs Complex IV activity	Complex IV functional marker
	MT‑CO1	Mitochondrially encoded cytochrome c oxidase subunit 1	Catalytic subunit of Complex IV	Reflects impaired oxidative phosphorylation	Respiratory chain damage marker
ATP Synthesis Dysfunction	ATP5A	ATP synthase F1 subunit alpha	Catalyzes ATP production through oxidative phosphorylation	Mitochondrial dysfunction reduces ATP synthesis capacity	Mitochondrial energy metabolism marker
Mitochondrial Structural and Functional Damage	TOM20	Translocase of outer mitochondrial membrane 20	Mediates mitochondrial protein import and reflects mitochondrial mass	Indicates mitochondrial structural alteration	Mitochondrial integrity marker
	VDAC1	Voltage‑dependent anion‑selective channel protein 1	Regulates mitochondrial metabolite exchange	Reflects mitochondrial membrane damage	Mitochondrial damage marker
Oxidative Stress Response	4‑HNE	4‑Hydroxynonenal	Lipid peroxidation product	Indicates oxidative membrane damage caused by mitochondrial dysfunction	Lipid oxidative damage marker
	8‑OHdG	8‑Hydroxy‑2'‑deoxyguanosine	Marker of oxidative DNA damage	Reflects oxidative stress‑induced DNA injury	DNA oxidative damage marker
Terminal Stress Response	p‑AMPK	Phosphorylated AMP‑activated protein kinase	Regulates cellular energy stress response	Activated during ATP depletion and metabolic stress	Energy stress indicator
	ATF4	Activating transcription factor 4	Regulates integrated stress response	Indicates mitochondrial and metabolic stress	Stress response marker
	CHOP	C/EBP homologous protein	Mediates stress‑induced cell death signaling	Reflects severe cellular stress and death response	Terminal stress marker

1.3 Application Scheme

Functional Module	Marker
Mn²⁺ accumulation	ICP‑MS Mn²⁺, SLC39A8, SLC30A10
Core node of Mnoptosis	COQ7
Impaired CoQ metabolism	CoQ10
ETC injury	COX4, NDUFS1
Defective ATP production	ATP5A, ATP level
Mitochondrial function	JC‑1/TMRE, OCR
Exclude ferroptosis	GPX4
Exclude cuproptosis	FDX1/DLAT
Exclude apoptosis	Cleaved‑Caspase3

1.4 References

1. Hu H, Chen Z, Li Y, Peng J, Cao J, Zhou H, Wang M, Du Y, Wu H, Zhao H, Huang S, Yu D, Liu M, Shevchenko OV, Matveeva NY, Yang Y, Huang K, Lv D, Min J, Chen L, Wang F. Metal‑dependent regulated cell death: Molecular architecture and translational frontiers. Imeta. 2026 Jul 6;5(3):e70141. doi: 10.1002/imt2.70141. PMID: 42491529; PMCID: PMC13377419.