Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity

Ramachandran, Prasanna Venkatesh; Savini, Marzia; Folick, Andrew; Hu, Kuang Yu; Masand, Ruchi; Graham, Brett H.; Wang, Meng C.

doi:10.1016/j.devcel.2018.12.022

Cited by 85 publications

(81 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…to induce and regulate a complex signaling network between mitochondria, the nucleus (Quiros et al, 2016), other organelles, such as lysosomes (Ramachandran et al, 2019), and the cytosol (D'Amico et al, 2017), resulting in increased cell stress resistance that can improve health and extend lifespan. Of particular interest is the recent observation that early developmental transient redox stress in Caenorhabditis elegans could indeed modify the methylation state of the genome, and lead to increased stress resistance, improved redox homeostasis, and prolonged lifespan (Bazopoulou et al, 2019).…”

Section: Ros and Mitochondria In Aging Progressionmentioning

confidence: 99%

Do You Remember Mitochondria?

2020

View full text Add to dashboard Cite

Dementia is one among the consequences of aging, and amnesia is often one of the most common symptoms. The lack of memory, as a consequence of both "healthy" aging or neurodegenerative conditions, such as in Alzheimer's disease, has a dramatic impact on the patient's lifestyle. In fact, the inability to recall information made by a previous experience could not only alter the interaction with the environment, but also lead to a loss of identity. Mitochondria are key regulators of brain's activity; thanks to their "dynamic organelles" nature they constantly rearrange in the cell body and move along axons and dendrites, changing in dimension, shape, and location, accordingly to the cell's energy requirements. Indeed, the energy they can provide is essential to maintain synaptic plasticity and to ensure transmission through presynaptic terminals and postsynaptic spines. Stressful conditions, like the ones found in neurodegenerative diseases, seriously impair mitochondria bioenergetic, leading to both loss of proper neuronal interaction and of neuron themselves. Here, we highlighted the current knowledge about the role of mitochondria and mitochondrial dynamics in relation to neurodegenerative disorders linked to aging. Furthermore, we discuss the obstacles as well as the future perspectives aimed to enlarge our knowledge about mitochondria as target for new therapeutic strategies to slow down aging and neurodegenerative disease's symptoms.

show abstract

Section: Ros and Mitochondria In Aging Progressionmentioning

confidence: 99%

Do You Remember Mitochondria?

2020

View full text Add to dashboard Cite

show abstract

“…Additionally, the lipase LIPL-4 promotes longevity in Caenorhabditis elegans by harnessing its degradative activity within the lysosome to establish a lipid–protein chaperone complex that translocates to the nucleus and promotes the transcriptional activity of NHR-49 and NHR-80 nuclear hormone receptors ( Folick et al, 2015 ). Nuclear hormone receptors regulate the expression of genes related to mitochondrial metabolism and the oxidative stress response, a mechanism linked to organismal longevity due to downstream activation of mitochondrial ß-oxidation and ETC activity ( Folick et al, 2015 ; Ramachandran et al, 2019 ). Biochemical and high throughput metabolomic analyses revealed that the nuclear complex generated by LIPL-4 in C. elegans is comprised of the lipid species oleoylethanolamide (OEA) and the lipid chaperone LBP-8.…”

Section: Metabolic Organelle Network Regulate Stem Cell Fatementioning

confidence: 99%

“…Biochemical and high throughput metabolomic analyses revealed that the nuclear complex generated by LIPL-4 in C. elegans is comprised of the lipid species oleoylethanolamide (OEA) and the lipid chaperone LBP-8. All three elements of this signaling pathway are structurally or functionally conserved in mammals (LIPL-4 and NHR-80 are homologous to mammalian LIPA and HNF4, respectively; the mammalian lipid metabolism transcription factor PPARα is activated by OEA) ( Fu et al, 2003 ; Folick et al, 2015 ; Ramachandran et al, 2019 ), thus similar lysosome-nuclear signaling mechanisms are likely to impact cell fate determinant transcriptional programs in mammalian systems.…”

Section: Metabolic Organelle Network Regulate Stem Cell Fatementioning

confidence: 99%

“…Lysosomes also function as central players in coordinating supply and demand of critical molecules involved in bioenergetic signaling ( Zhang et al, 2011b ; Lim and Zoncu, 2016 ; Savini et al, 2019 ; Ballabio and Bonifacino, 2020 ). The signaling pathways and mechanisms that impact lysosome biogenesis and function are linked to many activities that implicate them as regulators of stem cell biology, including self-renewal and differentiation decisions, cell death, and organismal aging and longevity ( Ramachandran et al, 2019 ; Savini et al, 2019 ; Ballabio and Bonifacino, 2020 ). An important role for lysosomes in cell identity determination is emerging, yet the mechanisms by which they may drive metabolic reprogramming and impact cell fate specification, and if these activities are indeed linked, are unclear.…”

Section: Lysosomes As Regulators Of Stem Cell Identitymentioning

confidence: 99%

See 1 more Smart Citation

Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity

Julian

Stanford

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity. We will discuss the inter-organelle interactions, cell signaling pathways, and transcriptional regulatory mechanisms with which lysosomes engage and how these activities impact metabolic signaling. We will further review recent data that position lysosomes as critical regulators of cell identity determination programs and discuss the known or putative biological mechanisms. Finally, we will briefly highlight the potential impact of elucidating mechanisms by which lysosomes regulate stem cell identity on our understanding of disease pathogenesis, as well as the development of refined regenerative medicine, biomarker, and therapeutic strategies.

show abstract

“…Emerging evidence suggests that longevity is associated with a specific lipid profile characterized by an increased ratio of monounsaturated fatty acids (MUFAs) to polyunsaturated fatty acids (PUFAs), both in humans and in C. elegans (Schroeder and Brunet, 2015). However, even though these results might suggest that elevated levels of PUFAs may accelerate aging on their own, recent studies suggest that the increased abundance of specific PUFAs (arachidonic acid [AA] and dihomo-g-linolenic acid [DGLA]) or other bioactive lipids (oleoylethanolamide [OEA]) may independently, or through their role in a lipid signaling cascade, extend lifespan through their effects on autophagy, gene expression, and/or mitochondrial activity (Folick et al, 2015;O'Rourke et al, 2013;Ramachandran et al, 2019).…”

Section: Introductionmentioning

confidence: 99%