Regulated mechanisms of stem cell maintenance are key to preventing stem cell depletion and aging. While mitochondrial morphology plays a fundamental role in tissue development and homeostasis, its ...role in stem cells remains unknown. Here, we uncover that mitochondrial dynamics regulates stem cell identity, self-renewal, and fate decisions by orchestrating a transcriptional program. Manipulation of mitochondrial structure, through OPA1 or MFN1/2 deletion, impaired neural stem cell (NSC) self-renewal, with consequent age-dependent depletion, neurogenesis defects, and cognitive impairments. Gene expression profiling revealed ectopic expression of the Notch self-renewal inhibitor Botch and premature induction of transcription factors that promote differentiation. Changes in mitochondrial dynamics regulate stem cell fate decisions by driving a physiological reactive oxygen species (ROS)-mediated process, which triggers a dual program to suppress self-renewal and promote differentiation via NRF2-mediated retrograde signaling. These findings reveal mitochondrial dynamics as an upstream regulator of essential mechanisms governing stem cell self-renewal and fate decisions through transcriptional programming.
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•Mitochondrial dynamics regulates the fate and identity of stem cells•Mitochondrial dynamics regulates stem cell fate by modifying ROS signaling•ROS activate developmental gene expression via an NRF2-dependent retrograde pathway•Aberrant mitochondrial dynamics impairs stem cell self-renewal and maintenance
Khacho et al. report that mitochondrial dynamics regulates neural stem cell fate during development and in the adult mouse brain. Using acute loss-of-function approaches to uncouple mitochondrial bioenergetics from the fission/fusion machinery, they find that the latter independently regulates ROS levels upstream of NRF2. Thus, defects in mechanisms that maintain the pool of mitochondria also impair neural stem cell function, which has important implications for aging and neurodegenerative diseases.
Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known ...programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wlds protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration.
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•A MAPK cascade is a central pathway underlying pathological axon degeneration•Sarm1 is required for activation of the MAPK cascade in this degenerative response•Sarm1-MAPK pathway triggers a local energy deficit in axons leading to degeneration•CytoNmnat1/Wlds and AKT converge on the MAPK cascade to regulate axon degeneration
This study delineates a MAPK cascade as the central pathway downstream of the adaptor protein Sarm1 in promoting pathological axonal death after injury. Early activation of the Sarm1-MAPK pathway in response to axonal damage triggers a local energy deficit that leads to final activation of calpains and breakdown of axonal.
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson’s disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified ...Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2. Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2–G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2–G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2–WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.
Neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membranes of activated neutrophils. NETs are found in a variety of conditions such as infection, malignancy, ...atherosclerosis, and autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. Studies suggest that an imbalance between “NETosis,” which is a process by which NETs are formed, and NET degradation may be associated with autoimmune diseases. Neutrophils, interleukin-8, ANCA and other inflammatory molecules are considered to play a key role in NET formation. Prolonged exposure to NETs-related cascades is associated with autoimmunity and increases the chance of systemic organ damage. In this review, we discuss the roles of various inflammatory molecules in relation to NETs. We also describe the role of NETs in the pathogenesis of autoimmune diseases and discuss the possibility of using targeted therapies directed to NETs and associated molecules to treat autoimmune diseases.
Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the ...consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase responsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1 responds dynamically to changes in energetic conditions to regulate cristae structure. This cristae regulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can still oligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 was required for resistance to starvation‐induced cell death, for mitochondrial respiration, for growth in galactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. We identified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacological and genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in which OPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrial architecture in a SLC25A protein‐dependent manner.
Synopsis
Metabolic stress causes inner mitochondrial membrane fusion protein OPA1 to interact with solute carriers and to oligomerize to regulate cristae shape, thereby maintaining mitochondrial activity under low energy availability.
OPA1 dynamically responds to energy substrate availability, mediating changes in cristae ultrastructure.
OPA1‐mediated cristae changes are required for cell adaptation to metabolic demand, independently of OPA1 fusion activity.
SLC25A proteins interact with OPA1 and modulate its function.
OGC (SLC25A11) affects how OPA1 oligomerizes in response to starvation, mediating changes in mitochondrial function.
Metabolic stress causes inner mitochondrial membrane fusion protein OPA1 to interact with solute carriers and to oligomerize to regulate cristae shape, thereby maintaining mitochondrial activity under low energy availability.
We use data collected from panel phone surveys to document the changes in food security of households in rural Liberia and Malawi during the market disruptions associated with the COVID-19 lockdowns ...in 2020. We use two distinct empirical approaches in our analysis: (a) an event study around the date of the lockdowns (March to July 2020), and (b) a difference-in-differences analysis comparing the lockdown period in 2020 to the same months in 2021, in order to attempt to control for seasonality. In both countries, market activity was severely disrupted and we observe declines in expenditures. However, we find no evidence of declines in food security.
Programmed cell death in Parkinson's disease Venderova, Katerina; Park, David S
Cold Spring Harbor perspectives in medicine,
2012-Aug-01, 20120801, Letnik:
2, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Parkinson's disease is a debilitating disorder characterized by a progressive loss of dopaminergic neurons caused by programmed cell death. The aim of this review is to provide an up-to-date summary ...of the major programmed cell death pathways as they relate to PD. For a long time, programmed cell death has been synonymous with apoptosis but there now is evidence that other types of programmed cell death exist, such as autophagic cell death or programmed necrosis, and that these types of cell death are relevant to PD. The pathways and signals covered here include namely the death receptors, BCL-2 family, caspases, calpains, cdk5, p53, PARP-1, autophagy, mitophagy, mitochondrial fragmentation, and parthanatos. The review will present evidence from postmortem PD studies, toxin-induced models (especially MPTP/MPP+, 6-hydroxydopamine and rotenone), and from α-synuclein, LRRK2, Parkin, DJ-1, and PINK1 genetic models of PD, both in vitro and in vivo.
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