Mitochondrial health, the epigenome and healthspan

Abstract

Food nutrients and metabolic supply-demand dynamics constitute environmental factors that interact with our genome influencing health and disease states. These gene–environment interactions converge at the metabolic-epigenome-genome axis to regulate gene expression and phenotypic outcomes. Mounting evidence indicates that nutrients and lifestyle strongly influence genome-metabolic functional interactions determining disease via altered epigenetic regulation. The mitochondrial network is a central player of the metabolic-epigenome-genome axis, regulating the level of key metabolites (NAD+, AcCoA, ATP) acting as substrates/cofactors for acetyl transferases, kinases (e.g., protein kinase A), deacetylases (e.g., sirtuins). The chromatin, an assembly of DNA and nucleoproteins, regulates the transcriptional process, acting at the epigenomic interface between metabolism and the genome. Within this framework, we review existing evidence showing that preservation of mitochondrial network function is directly involved in decreasing the rate of damage accumulation thus slowing aging and improving healthspan.

Inorganic polyphosphate enhances radio-sensitivity in a human non–small cell lung cancer cell line, H1299

“…32 Therefore, we hypothesize that polyP might affect the mitochondrial ATP metabolism, such as ATP synthase activity, ATPase activity, and adenylate kinase activity. PolyP also plays an essential role in mitochondrial ion transport by regulating the mPTP, 33 while mPTP opening is strongly associated with cell death. 34 Furthermore, Elustondo et al 23 reported that the composition of the ATPase C-subunit, polyhydroxybutyrate, and polyP is required for the mPTP opening.…”

Mitochondrial-epigenetic crosstalk in environmental toxicology

“…Mitochondrial metabolites can serve as substrates for reactions that modify DNA [4]. In addition, biomolecules whose abundance or redox status respond to mitochondrial activity can serve as metabolic sensors for nuclear chromatin responses [4].…”

“…In addition, biomolecules whose abundance or redox status respond to mitochondrial activity can serve as metabolic sensors for nuclear chromatin responses [4]. These metabolites and “energy sensors” are essential for cross-compartment communication, so much so that some hypothesize an ancient evolutionary origin of these mechanisms [1].…”

“…The majority (1500–2000) of mitochondrial proteins are encoded in the nuclear genome, so programmed communication among nuclear, cytoplasmic, and mitochondrial compartments is essential for maintaining cellular health [4, 5]. Two main signaling systems exist: nuclear signaling to the mitochondria [ anterograde signaling ], best described in regulation of oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in response to environmental signals received by the nucleus, and mitochondrial signals to the nucleus [ retrograde signaling ] (reviewed in [6]).…”

“…Two main signaling systems exist: nuclear signaling to the mitochondria [ anterograde signaling ], best described in regulation of oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in response to environmental signals received by the nucleus, and mitochondrial signals to the nucleus [ retrograde signaling ] (reviewed in [6]). Both signaling systems can communicate intracellular energy needs or a need to compensate for dysfunction to maintain homeostasis, but both can also relay inappropriate signals in the presence of dysfunction in either system and contribute to adverse health outcomes [4, 5]. We will first review the two main signaling systems and highlight known or biologically feasible epigenetic contributions to both, then briefly discuss the emerging field of epigenetic regulation of the mitochondrial genome , and finally discuss putative “crosstalk phenotypes” , including biological phenomena, such as caloric restriction, maintenance of stemness, and circadian rhythm, and states of disease or loss of function, such as cancer and aging, in which both the nuclear epigenome and mitochondria are strongly implicated.…”