bims-mitinf 2019-01-27 papers

Cell Rep. 2019 Jan 22. pii: S2211-1247(18)32076-X. [Epub ahead of print]26(4): 945-954.e4

Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging.

Hanzhi Luo, Wei-Chieh Mu, Rajendra Karki, Hou-Hsien Chiang, Mary Mohrin, Jiyung J Shin, Rika Ohkubo, Keisuke Ito, Thirumala-Devi Kanneganti, Danica Chen.

Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD+-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.

Keywords: NLRP3; SIRT2; SIRT3; SIRT7; aging; clonal hematopoiesis; hematopoietic stem cell; inflammasome; mitochondrial UPR; oxidative stress

DOI: https://doi.org/10.1016/j.celrep.2018.12.101

Cell Mol Life Sci. 2019 Jan 23.

Mitochondrial stress triggers a pro-survival response through epigenetic modifications of nuclear DNA.

Lía Mayorga, Betiana N Salassa, Diego M Marzese, Mariana A Loos, Hernán D Eiroa, Fabiana Lubieniecki, Clara García Samartino, Patricia S Romano, María Roqué.

Mitochondrial dysfunction represents an important cellular stressor and when intense and persistent cells must unleash an adaptive response to prevent their extinction. Furthermore, mitochondria can induce nuclear transcriptional changes and DNA methylation can modulate cellular responses to stress. We hypothesized that mitochondrial dysfunction could trigger an epigenetically mediated adaptive response through a distinct DNA methylation patterning. We studied cellular stress responses (i.e., apoptosis and autophagy) in mitochondrial dysfunction models. In addition, we explored nuclear DNA methylation in response to this stressor and its relevance in cell survival. Experiments in cultured human myoblasts revealed that intense mitochondrial dysfunction triggered a methylation-dependent pro-survival response. Assays done on mitochondrial disease patient tissues showed increased autophagy and enhanced DNA methylation of tumor suppressor genes and pathways involved in cell survival regulation. In conclusion, mitochondrial dysfunction leads to a "pro-survival" adaptive state that seems to be triggered by the differential methylation of nuclear genes.

Keywords: Apoptosis; Autophagy; DNA methylation; Mitochondrial diseases; Mitochondrial dysfunction; Stress response; Survival

DOI: https://doi.org/10.1007/s00018-019-03008-5

Sci Rep. 2019 Jan 24. 9(1): 727

Pomegranate activates TFEB to promote autophagy-lysosomal fitness and mitophagy.

Sijie Tan, Chye Yun Yu, Zhi Wei Sim, Zun Siong Low, Brianna Lee, Faith See, Nyo Min, Archana Gautam, Justin Jang Hann Chu, Kee Woei Ng, Esther Wong.

Mitochondrial dysfunction underscores aging and diseases. Mitophagy (mitochondria + autophagy) is a quality control pathway that preserves mitochondrial health by targeting damaged mitochondria for autophagic degradation. Hence, molecules or compounds that can augment mitophagy are therapeutic candidates to mitigate mitochondrial-related diseases. However, mitochondrial stress remains the most effective inducer of mitophagy. Thus, identification of mitophagy-inducing regimes that are clinically relevant is favorable. In this study, pomegranate extract (PE) supplementation is shown to stimulate mitophagy. PE activates transcription factor EB (TFEB) to upregulate the expression of autophagy and lysosomal genes for mitochondrial quality control under basal and stress conditions. Basally, PE alters mitochondrial morphology and promotes recruitment of autophagosomes to the mitochondria (mitophagosome formation). Upon onset of mitochondrial stress, PE further augments mitophagosome formation, and engages PINK1 and Parkin to the mitochondria to potentiate mitophagy. This cellular phenomenon of PE-induced mitophagy helps to negate superfluous mitochondrial reactive oxygen species (ROS) production and mitochondrial impairment. Overall, our study highlights the potential of PE supplementation as a physiological therapy to modulate TFEB activity to alleviate mitochondrial dysfunction in aging and mitochondrial-related diseases.

DOI: https://doi.org/10.1038/s41598-018-37400-1