C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress

Melentijevic, Ilija; Tóth, Márton L.; Arnold, Meghan Lee; Guasp, Ryan J.; Harinath, Girish; Nguyen, Ken; Taub, Daniel G.; Parker, J. Alex; Néri, Christian; Gabel, Christopher V.; Hall, David H.; Driscoll, Monica

doi:10.1038/nature21362

Cited by 330 publications

(477 citation statements)

References 50 publications

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“…There are also important roles in cellular differentiation and cell type-specific differences (Lu et al 2013; Scarpulla 2011). In a particularly remarkable example, while mitophagy is generally viewed as a process that occurs within cells, recent evidence indicates that in some cases, mitochondria may be exported to another cell or extracellular space via “exosomes” (Torralba et al 2016) or “exophers” (Melentijevic et al 2017), potentially rescuing function in a damaged cell. For example, astrocytes can digest mitochondria from neighboring axons (“transcellular mitophagy”) (Davis et al 2014).…”

Section: Mitochondrial Dynamics: Fusion and Fission Transport Bimentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.

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Section: Mitochondrial Dynamics: Fusion and Fission Transport Bimentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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“…A possible solution to the conundrum comes from the observation of mitochondria in vivo , rather than in cultures of isolated neurons as recently reported for C. elegans (Melentijevic et al, 2017). For some years, the researchers noted that fluorescently labeled components of the six gentle touch neurons of C. elegans were found outside the cell particularly during some stages of life.…”

Section: Mitochondrial Dynamics Defined By Five Phenomenamentioning

confidence: 99%

“…For some years, the researchers noted that fluorescently labeled components of the six gentle touch neurons of C. elegans were found outside the cell particularly during some stages of life. Using microscopy and genetics, they found that whole mitochondrial organelles as well as protein aggregates, including neurotoxic aggregates of Huntingtin polyQ protein (Htt-Q128), were released from neurons in large membrane-bound structures approximately the size of the cell soma, which they refer to as exophers (Melentijevic et al, 2017). By unknown mechanisms, exophers appear to preferentially package damaged over healthy mitochondria and aggregating fluorescent proteins over non-aggregating versions (Melentijevic et al, 2017) (see section 7.4 ).…”

Section: Mitochondrial Dynamics Defined By Five Phenomenamentioning

confidence: 99%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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“…Hence, the accumulation of dysfunctional organelles, misfolded proteins or the subsequent generation of aggresomes may either be tolerated in aged organisms to some degree or disposed of by a different clearance mechanism. A recent study in C. elegans has shown that protein aggregates and organelles existing in neurons can be internalized into vesicles, so-called exophers, which are transmitted into the sourrounding tissues 12 . Importantly, this extrusion mechanism seems to specifically operate when autophagy or the UPS are inhibited 12 .…”

mentioning

confidence: 99%

“…A recent study in C. elegans has shown that protein aggregates and organelles existing in neurons can be internalized into vesicles, so-called exophers, which are transmitted into the sourrounding tissues 12 . Importantly, this extrusion mechanism seems to specifically operate when autophagy or the UPS are inhibited 12 . It could therefore represent a salvage pathway during age-related stress conditions, in which the autophagic flux and proteasomal degradation are dysfunctional.…”

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confidence: 99%

The dire side of autophagy in aging: Lessons from C. elegans

Medina

Richly

2017

Communicative & Integrative Biology

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Autophagy is an essential cellular process that eliminates cellular debris, dysfunctional organelles and misfolded proteins thereby maintaining cellular metabolism and homeostasis. Functional autophagy is generally thought to counteract aging and is crucial for the prolonged lifespan and health of an animal. Whereas this statement is true for young animals, we have recently shown that autophagy becomes dysfunctional in post-reproductive C. elegans contributing to aging and neurodegeneration. Downregulation of autophagy nucleation in post-reproductive nematodes causes a lifespan extension and preservation of neuronal integrity putting the generally accepted view of the role of autophagy in aging into question. Here we discuss specific cellular degradation programs in young and old animals and speculate on molecular mechanisms that might explain this unexpected role of autophagy in aged animals.

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C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress

Cited by 330 publications

References 50 publications

Mitochondrial fusion, fission, and mitochondrial toxicity

Mitochondrial fusion, fission, and mitochondrial toxicity

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

The dire side of autophagy in aging: Lessons from C. elegans

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