FIGURE 1: Mitochondria as communicating organelles. The figure illustrates some examples of how mitochondria communicate with the nucleus. This includes mitochondrial derived peptides (MDPs), metabolites or mitochondrial reactive oxygen species (mROS). Humanin’s cytoprotective function is mediated by its binding to Bax and IGFBP-3, preventing cellular apoptosis. Other MDPs include small humanin-like peptides (SHLPs), such as SHLP2, which specifically targets misfolded amyloid seeds to inhibit amyloid polypeptide misfolding. MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) are MDPs that promote metabolic homeostasis and prevent metabolic stress by its translocation to the nucleus, provided by the metabolic regulator AMPK. Mitochondria are also one of the main sources for acetyl-CoA, which is required by the histone acetyltransferases (HATs) for histone acetylation. Acetylation of histones results in a transcriptionally active chromatin configuration that promotes gene expression. Further, the tricarboxylic acid cycle (TCA) metabolite α-ketoglutarate (αKG) is the substrate of the histone demethylase ten-eleven translocation enzymes (TETs) which demethylate the K27me3 and K4me3 histone 3 tails. Finally, mROS are generated primarily by the complexes I and III of the electron transport chain, and are then able to diffuse into the cytoplasm to activate various signaling pathways, and regulate the expression of specific genes.