Mammalian Lysophagy: mechanisms and pathophysiological implications

Lysosomes are the cell's primary recycling centres, but they can be damaged by a wide range of stresses — from misfolded protein aggregates and bacterial invasion to crystalline particles like cholesterol or uric acid crystals and chemical toxins. When a lysosome is injured, the cell must decide quickly whether to patch the membrane, destroy the whole organelle, or generate new ones. This review maps out the molecular decision-making process, centred on a pathway called lysophagy — a specialised form of autophagy (cellular self-eating) dedicated to recognising and disposing of damaged lysosomes. The process begins when the lysosome's interior sugars become exposed on the cytoplasmic face of the broken membrane, acting as an 'eat-me' signal that is then amplified by ubiquitin tags and read by dedicated autophagy receptor proteins. These receptors recruit the core autophagy machinery to wrap the damaged lysosome in a double membrane and deliver it for destruction. The review also explains how lysophagy is wired into broader cellular stress responses, including membrane-repair systems, nutrient-sensing pathways and innate immunity. Because dysfunctional lysosomal quality control appears in neurodegeneration, cancer, infection and chronic inflammation, understanding lysophagy opens therapeutic windows across multiple disease areas.

• Lysosomal membrane permeabilization (LMP) exists on a continuum — from transient nanoscale pores that can be repaired to full catastrophic rupture — and the cell's response is calibrated to the severity of damage rather than being an all-or-nothing switch.
• Damage recognition is hierarchical: exposed lumenal glycans (sensed by cytosolic lectins such as Galectin-3) are detected first, followed by ubiquitin-dependent tagging of the damaged membrane that recruits selective autophagy receptors (e.g., p62/SQSTM1, TAX1BP1, NDP52) to activate autophagosome nucleation specifically around the injured lysosome.
• Lysophagy is mechanistically integrated with at least two other quality-control arms — membrane repair (via ESCRTs and phospholipid remodelling) and lysosomal regeneration (biogenesis controlled by TFEB/TFE3) — forming a coordinated triage network rather than an isolated degradation route.
• Dysregulated lysophagy has been causally implicated in the pathophysiology of neurodegenerative diseases, intracellular bacterial infections, tumour progression and chronic inflammatory disorders, positioning it as a convergent vulnerability point across disease categories.
• The review summarises emerging experimental tools for studying lysosomal quality control in mammalian cells, including galectin-puncta assays, lysosomal-damage reporter systems and pharmacological LMP inducers, offering a methodological roadmap for the field.

This is a comprehensive narrative and mechanistic review article (no primary experimental dataset), synthesising published literature on mammalian lysophagy. The authors systematically cover damage-sensing mechanisms, ubiquitin-dependent receptor recruitment, autophagosome formation around injured lysosomes, crosstalk with membrane-repair and metabolic-signalling pathways, and disease associations. Experimental models discussed span cell-free biochemical assays, cultured mammalian cell lines treated with established LMP inducers (e.g., L-leucyl-L-leucine methyl ester, silica, lysosomotropic agents), and in vivo genetic models. No patient cohorts or clinical trial data are included.

As a review, this article cannot establish causality or effect sizes between lysophagy dysregulation and specific disease outcomes; all mechanistic claims depend on the quality and model-system limitations of the primary studies cited. The field currently lacks standardised, quantitative in vivo readouts of lysophagy flux in intact tissues, making it unclear how well cell-culture findings translate to physiologically relevant contexts. Key open questions the authors identify include the precise hierarchy and redundancy among autophagy receptors at damaged lysosomes, and the molecular checkpoints that determine repair versus degradation decisions at different LMP severities. Clinical translation remains premature until selective lysophagy modulators with acceptable pharmacological profiles are developed and tested in disease-relevant animal models.

This review extends [§37], which demonstrates that CHCHD2/10 protein aggregates are cleared through selective autophagy via GABARAP receptors, by providing the broader mechanistic framework within which such receptor-mediated selective autophagy operates at damaged organelles — the same ubiquitin-tagging and receptor-recruitment logic applies whether the cargo is a protein aggregate or an injured lysosome. It parallels [§81], which examines FOXO transcription factors in Alzheimer's disease and their regulation of autophagy and mitochondrial quality control, because both articles converge on the idea that failure of organelle-specific quality-control programmes is a shared driver of neurodegeneration. The lysophagy–TFEB/TFE3 biogenesis axis discussed here also directly contextualises [§129], which shows that MITF (a TFEB-family member) is essential for autophagy in retinal pigment epithelium, since MITF/TFEB activity governs both lysosomal regeneration after damage and baseline autophagic capacity. Collectively, these articles reinforce a corpus-wide theme on Bionoia: selective autophagy sub-types (mitophagy, aggrephagy, lysophagy) share a conserved receptor-recruitment logic but diverge in upstream damage-sensing steps, and their failure contributes to a spectrum of chronic diseases from neurodegeneration to cancer.

• CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs
  Shares the core mechanistic logic of ubiquitin-dependent selective autophagy receptor recruitment (GABARAPs for aggregate clearance vs. p62/NDP52 for lysosomal clearance), making direct comparison clarifying for readers mapping receptor specificity across cargo types.
• FOXO transcription factors in Alzheimer's Disease: balancing neuroprotection and neuronal degeneration
  Both articles converge on autophagy and organelle quality control as neuroprotective mechanisms in neurodegeneration; comparing them illustrates how FOXO-regulated transcriptional programmes and lysophagy machinery interact at the disease-pathway level.
• MITF is essential for autophagy in the retinal pigment epithelium
  MITF's role in driving autophagy in retinal epithelium parallels the TFEB/TFE3 lysosomal biogenesis axis reviewed here; juxtaposing the two clarifies how transcription-factor-driven lysosomal renewal complements lysophagic removal of damaged organelles.
• PRRSV NSP2 hijacks host lipophagy via a LIPE-PNPLA2-AMPK-MTOR axis to promote viral replication
  PRRSV NSP2 hijacking of host lipophagy via AMPK-MTOR signalling represents a pathogen subversion of selective autophagy, directly relevant to the lysophagy–innate immune crosstalk discussed in this review, and offers a concrete virological case study.
• Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic potential
  Metformin activates AMPK-mTOR signalling to modulate autophagy in metabolic liver disease, providing a pharmacological angle on the metabolic-signalling nodes (mTOR, AMPK) that this review identifies as key regulators of lysosomal fate decisions.