Mitochondrial-to-nuclear communication in aging: an epigenetic perspective

Zhu, Di; Li, Xinyu; Tian, Ye

doi:10.1016/j.tibs.2022.03.008

Cited by 63 publications

(36 citation statements)

References 125 publications

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“…Emerging evidence suggests that dysfunctional mitochondrial metabolites relay signals to the nucleus via mito-nuclear communication, which further alters the epigenetic regulation of genes associated with aging 47, 48 . Thus, the observed alterations in epigenetic modifications in HGPS and MADA may not solely be due to disruptions in the nuclear lamina, and may also be impacted indirectly by mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia

Padhiar

Yang

et al. 2022

Preprint

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Homozygous lamina/c p.R527C mutations result in severe mandibuloacral dysplasia (MAD) and progeroid syndrome, but the underlying molecular pathology remains unknown. Here, we report on three patients with MAD, all displaying severe systemic inflammaging and characterized the major molecular pathways involved in the manifestation of this disease. Analysis of induced pluripotent stem cell (IPSC)-derived mesenchymal stem cells (MAD-iMSCs) obtained from the patients revealed that increased mitochondrial Ca+2 loading was the root cause of lost mitochondrial membrane potential, abnormal fission/fusion and fragmentation, which then participated in inflammaging by inducing the inflammasome. These alterations in Ca+2 homeostasis were mediated by signal transducer and activator of transcription 3 (STAT3), which is located on the mitochondrial associated membrane (MAM). STAT3 function could be rescued by treatment with clinically-approved IL-6 blockers, or by correction of R527C mutations. In addition, extracellular vesicles (EVs) obtained from MAD-iMSCs displayed reduced immunomodulatory function, being unable to rescue bleomycin-induced lung fibrosis and triggering mitochondrial dysfunction, senescence, and fibrosis in healthy cells. Our results provide new insights into the pathology of complex lamin-associated MAD with systemic immunosenescence, and suggest that targeting defective mitochondrial Ca+2 homeostasis may represent a promising novel therapy for this condition.

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Section: Discussionmentioning

confidence: 99%

MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia

Padhiar

Yang

et al. 2022

Preprint

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“…Mitochondria are the powerhouses of the cell, as they generate most of the ATP required by the cell. The brain is a highly metabolic organ and neurons in the central nervous system have an intense demand for mitochondria [ 44 ]. As such, the suppressed expression of mtTFA in the brain tissues of rats treated with LPS may indicate a decreased mitochondrial biogenesis and mitochondrial DNA replication and transcription that may lead to mitochondrial dysfunction and neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective and Antioxidant Effects of Nanocurcumin Oral Suspension against Lipopolysaccharide-Induced Cortical Neurotoxicity in Rats

et al. 2022

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Lipopolysaccharide (LPS) proved to be an important tool, not only in the induction of neuroinflammatory models, but also in demonstrating the behavioral and cognitive consequences of endotoxemia. Curcumin, in its native form, has proven to be a worthy candidate for further development as it protects the dopaminergic neurons against LPS-induced neurotoxicity. However, it remains hindered by its poor bioavailability. In this study we aim to explore the possible molecular mechanism of LPS-induced neurotoxicity and the possible protective effects of orally supplemented nanocurcumin. Thirty-six adult male Wistar rats weighing 170–175 g were divided into six groups and treated with single I.P. (intra-peritoneal) dose of LPS (sigma and extracted; separately) (5 mg/kg BW) plus daily oral nanocurcumin (15 mg/kg BW). The rats were followed for 7 days after the LPS injection and nanocurcumin supplementations daily via oral gavage. After scarification, the levels of neurotransmitters, antioxidants, and amyloidogenesis markers were assessed in brain tissues. Nanocurcumin showed adequate antioxidant and neuroprotective effects, rescuing the rats which had been injected intraperitoneally with LPS endotoxin.

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“…Conversely, the downregulated GPR19 data cohorts were more strongly associated with ‘Interleukin signaling’, ‘mTOR signaling’, ‘IGF-1 signaling’ and ‘Nuclear Laminopathies’. All of these diverse functions strongly converge with respect to the pathomechanisms linked to pathological aging (DNA damage—[ 73 ]; Cholesterol regulation [ 188 , 189 , 190 ]; stem cell management [ 191 , 192 ]; UPR [ 193 , 194 ]; mTOR signaling [ 195 , 196 ]; IGF-1 signaling [ 197 , 198 ]; laminopathies [ 199 , 200 ]).…”

Section: Functional Gpr19 Molecular Signaturesmentioning

confidence: 99%

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

Maudsley

Walter

Schrauwen

et al. 2022

IJMS

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G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology.

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Mitochondrial-to-nuclear communication in aging: an epigenetic perspective

Cited by 63 publications

References 125 publications

MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia

MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia

The Neuroprotective and Antioxidant Effects of Nanocurcumin Oral Suspension against Lipopolysaccharide-Induced Cortical Neurotoxicity in Rats

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

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Mitochondrial-to-nuclear communication in aging: an epigenetic perspective

Cited by 63 publications

References 125 publications

MAM-STAT3-induced upregulation of mitochondrial Ca+2 causes immunosenescence in patients with type A mandibuloacral dysplasia

MAM-STAT3-induced upregulation of mitochondrial Ca+2 causes immunosenescence in patients with type A mandibuloacral dysplasia

The Neuroprotective and Antioxidant Effects of Nanocurcumin Oral Suspension against Lipopolysaccharide-Induced Cortical Neurotoxicity in Rats

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

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MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia

MAM-STAT3-induced upregulation of mitochondrial Ca⁺² causes immunosenescence in patients with type A mandibuloacral dysplasia