Damaged lysosomes undergo budding-type fission driven by mitochondrial vesicles

In a discovery that reshapes how biologists think about cellular quality control, researchers have identified an entirely new mechanism by which cells repair their damaged lysosomes. The process, termed budding-type fission, or B-fission, allows a compromised lysosome to bud off small, membrane-enclosed structures that scission away and mature into fully functional daughter organelles. Remarkably, the machinery driving this renewal is borrowed from a completely different organelle: the mitochondrion. The study, published in Nature Cell Biology, reveals an unexpected communication highway between mitochondria and lysosomes that becomes critical when cells are starved of oxygen and then reoxygenated, as happens during a heart attack or stroke.

Lysosomes are often described as the recycling centers of the cell. These acidic, membrane-bound compartments contain a cocktail of degradative enzymes capable of breaking down proteins, lipids, damaged organelles, and other cellular debris into their basic building blocks, which can then be reused. Because nearly every cellular waste stream ultimately passes through the lysosome, even partial impairment of these organelles can cascade into widespread dysfunction. Lysosomal damage is a hallmark of aging, neurodegenerative disease, and ischemia-reperfusion injury, the tissue damage that occurs when blood supply returns to tissue after a period of oxygen deprivation. Yet despite decades of research into lysosome biology, the mechanisms that maintain lysosomal integrity under stress have remained incompletely understood.

The prevailing models of lysosomal maintenance have centered on autophagic lysosome reformation, a process in which lysosomal components are salvaged from autolysosomes, hybrid compartments formed when autophagosomes fuse with lysosomes, and reassembled into new functional lysosomes. The new study demonstrates that B-fission operates independently of this canonical pathway. When lysosomes are damaged by hypoxia-reoxygenation stress, they do not simply wait to be recycled through autophagy. Instead, they actively participate in their own rescue, generating membrane buds on their surface. These buds progressively extend from the parent organelle and then undergo scission, pinching off to yield small, fully functional lysosomes. The undamaged components of the impaired parent organelle are thereby reorganized into daughter organelles, leaving the damaged material behind to be dealt with separately.

The mechanistic heart of the discovery lies in the identity of the scission machinery. Budding and fission events in cells generally require a specific set of proteins to constrict and sever a membrane neck. For mitochondria, that machinery is well known: the dynamin-related GTPase DRP1, recruited to the mitochondrial outer membrane by adaptor proteins such as MFF, constricts and divides mitochondria during mitochondrial fission. The researchers found that damaged lysosomes co-opt this exact mitochondrial division apparatus. MFF, a fission adaptor normally resident on mitochondria, is delivered to lysosomes, where it recruits DRP1 to drive the scission of the budding lysosomal membrane. In other words, the cell repurposes the mitochondrial division machinery to divide a completely different organelle.

How does MFF get to lysosomes in the first place? The answer involves mitochondrial-derived vesicles, or MDVs. These small vesicles bud from mitochondria and are known to transport selected mitochondrial cargo to other cellular destinations, most notably to peroxisomes and to autophagosomes during mitophagy. The new work shows that under hypoxia-reoxygenation stress, mitochondria generate MDVs carrying MFF. These MFF-positive vesicles then travel to damaged lysosomes and deliver their cargo, providing the adaptor that lysosomes need to assemble a functional DRP1-dependent scission apparatus. This is a striking example of organelle-to-organelle communication, with mitochondria effectively supplying the tools that allow lysosomes to renew themselves.

Two additional proteins complete the regulatory circuit. The first is MIRO2, a mitochondrial outer-membrane GTPase better known for its role in linking mitochondria to microtubule-dependent motor proteins and regulating mitochondrial motility. The study shows that MIRO2 promotes the formation of MFF-positive MDVs through a direct physical interaction with MFF, acting as a gatekeeper that selects MFF as cargo for vesicular export. The second is ITM2C, a lysosomal membrane protein that binds MIRO2. By tethering the MFF-carrying vesicles to the lysosomal surface, ITM2C guides and anchors them at the correct destination, ensuring efficient MFF delivery and, consequently, efficient B-fission. The researchers describe this stress-responsive pathway as the ITM2C–MIRO2–MFF–DRP1 axis, a chain of interactions that connects the mitochondrial surface to the lysosomal scission machinery.

The physiological relevance of this pathway was demonstrated through manipulation of AMPK, the AMP-activated protein kinase, a master metabolic sensor that is activated when cellular energy levels fall. When cells were treated with AMPK activators such as 991 or metformin under normal oxygen conditions, MFF-dependent lysosomal B-fission was promoted, indicating that AMPK is a physiological trigger for the pathway. Conversely, when AMPK was inhibited with dorsomorphin during hypoxia-reoxygenation, B-fission was suppressed, and lysosomes presumably remained in their damaged state. This pharmacological control establishes AMPK as a central node that couples energy stress to lysosomal renewal, and it raises the intriguing possibility that widely used drugs such as metformin may partially exert their protective effects by boosting this lysosome-repair program.

The implications of the work extend across multiple fields. For researchers studying ischemia-reperfusion injury, the identification of a stress-activated lysosomal renewal pathway offers a mechanistic explanation for why lysosomal damage is so consequential during heart attack and stroke, and it suggests that enhancing B-fission pharmacologically could protect vulnerable tissues. For the lysosome biology community, the finding adds a new mode of organelle maintenance to the established repertoire of autophagic lysosome reformation and endosomal sorting. And for cell biologists more broadly, the demonstration that MDVs can ferry a fission adaptor between organelles, and that a mitochondrial division machine can be installed on lysosomes, underscores how fluid the boundaries between organelle systems really are. Mitochondria, long appreciated as signaling hubs that communicate through calcium, reactive oxygen species, and metabolites, now appear to communicate through physical transport of division machinery as well.

The technical elegance of the study lies in its dissection of each step of the pathway. By showing that MIRO2 binds MFF directly, that MDVs carry MFF, that ITM2C tethers those vesicles to lysosomes, and that DRP1 recruitment to MFF-decorated lysosomes is required for scission, the authors built a complete causal chain from mitochondrial membrane to lysosomal division. Disrupting any single link, whether by removing MIRO2, ITM2C, MFF, or DRP1, or by blocking AMPK signaling, compromises the ability of stressed cells to regenerate functional lysosomes from damaged parents. Conversely, activating AMPK under baseline conditions is sufficient to initiate the program even without hypoxic stress.

What remains to be explored is the breadth of this phenomenon. Hypoxia-reoxygenation is a particularly well-defined stress, but lysosomal damage arises in many contexts, including exposure to aggregate-prone proteins in neurodegeneration, lipid overload in metabolic disease, and the normal wear of aging. Whether B-fission operates in neurons, in cardiomyocytes, and in aging tissues in vivo are pressing questions. There is also the tantalizing therapeutic prospect that metformin, already one of the most prescribed drugs in the world, could be repurposed or optimized to strengthen lysosomal quality control in diseases of lysosomal stress. For now, the study stands as a vivid demonstration that the cell’s repair strategies are more inventive than previously imagined: when a lysosome is damaged, the mitochondria deliver the scissors that let it cut its losses and begin again.