Disabled Macroautophagy Module

Metabolism Aging Module disabled_macroautophagy 8 disorders Pathograph 3

A conserved mechanism module for the hallmark of aging (Lopez-Otin et al., 2023) termed disabled macroautophagy: the age-associated decline of the macroautophagy machinery and the loss of its cytoplasmic quality-control function. Macroautophagy is the lysosomal degradation pathway - mediated by the evolutionarily conserved autophagy-related (ATG) genes - that sequesters and recycles dysfunctional organelles, aggregated proteins, and intracellular microbes, playing a fundamental role in cellular, tissue, and organismal homeostasis. Autophagic potential falls in normal and pathological aging; when ATG-mediated capture and lysosomal clearance fail, damaged cytoplasmic constituents accumulate, contributing to neurodegenerative, inflammatory, and other age-related disease. Because autophagy induction (by dietary restriction or nutrient-signaling inactivation) counteracts age-associated damage, restoring autophagic competence is a target for healthy-aging intervention. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific autophagy lesion (e.g. an ATG-pathway or autophagy-adaptor mutation, or secondary autophagy suppression) while preserving the conserved machinery-decline -> failed-clearance -> accumulated-damage chain.

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Pathophysiology Nodes

3 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"). This module treats macroautophagy COMPETENCE (the ATG machinery) as the hallmark itself, distinct from - but complementary to - the specific autophagy-related arms modeled elsewhere: deregulated_nutrient_sensing models mTORC1-driven autophagy SUPPRESSION as one downstream node, loss_of_proteostasis models autophagy as one aggregate-clearance route, and mitochondrial_dysfunction models mitophagy. Keep this module focused on the general macroautophagy pathway; route organelle- or substrate-specific claims to those modules. Key conformance target: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control".

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Used By Disorder Entries

Alzheimer Disease via Autophagy-Lysosomal Dysfunction → Failure of Cytoplasmic Quality Control , Neuronal Endosomal-Lysosomal Acidification Failure → Failure of Cytoplasmic Quality Control

Amyotrophic Lateral Sclerosis via Impaired Autophagy → Failure of Cytoplasmic Quality Control

Bethlem myopathy via Defective autophagic clearance of damaged organelles → Failure of Cytoplasmic Quality Control

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia via Defective ubiquitin-containing autophagosome maturation → Autophagy Machinery Decline

OPTN-related Open Angle Glaucoma via Impaired Autophagic Flux in Retinal Ganglion Cells → Failure of Cytoplasmic Quality Control

Parkinson's Disease via Autophagy-Lysosome Pathway Dysfunction → Failure of Cytoplasmic Quality Control

Spinocerebellar Ataxia, Autosomal Recessive 31 via Impaired Autophagosome Formation and Autophagic Flux → Failure of Cytoplasmic Quality Control

VCP-Associated Multisystem Proteinopathy via Defective autophagosome maturation → Autophagy Machinery Decline

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Pathograph

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Pathophysiology

Autophagy Machinery Decline

trigger

The macroautophagy pathway - autophagosome formation and lysosomal fusion, mediated by the conserved autophagy-related (ATG) genes - declines in capacity during normal and pathological aging. This reduced autophagic potential is the initiating lesion of the hallmark.

Macroautophagy GO:0016236 DECREASED Autophagosome Assembly GO:0000045 DECREASED

Used by disorders

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia as Defective ubiquitin-containing autophagosome maturation

VCP-Associated Multisystem Proteinopathy as Defective autophagosome maturation

Downstream

Failure of Cytoplasmic Quality Control

Failure of Cytoplasmic Quality Control

central effector

Autophagy selectively targets dysfunctional organelles, intracellular microbes, and pathogenic proteins for recycling, counteracting the age-associated accumulation of damaged organelles and proteins. When macroautophagy is disabled, this cytoplasmic quality-control and recycling function is lost - the central effector state that disease-specific autophagy lesions converge upon.

Autophagy GO:0006914 DECREASED

Used by disorders

Alzheimer Disease as Autophagy-Lysosomal Dysfunction

Alzheimer Disease as Neuronal Endosomal-Lysosomal Acidification Failure

Amyotrophic Lateral Sclerosis as Impaired Autophagy

Bethlem myopathy as Defective autophagic clearance of damaged organelles

OPTN-related Open Angle Glaucoma as Impaired Autophagic Flux in Retinal Ganglion Cells

Parkinson's Disease as Autophagy-Lysosome Pathway Dysfunction

Spinocerebellar Ataxia, Autosomal Recessive 31 as Impaired Autophagosome Formation and Autophagic Flux

Downstream

Accumulated Cellular Damage and Age-Related Disease