Role of FOXO transcription factors in crosstalk between mitochondria and the nucleus

FOXO transcription factors are evolutionally conserved regulators of organismal life span downstream of insulin signaling. After integrating cellular signals from various stimuli such as growth factors, oxidative stress, and energy deprivation, FOXO factors induce expression of a specific set of genes that regulate various cellular processes to maintain homeostasis at a cellular or organismal level. In this review, we discuss roles of FOXO proteins in the maintenance of mitochondria, organelles critical for cellular quality control. FOXO factors protect mitochondria by activating mitochondrial antioxidant enzymes and they help remodel damaged mitochondria by inducing remodeling processes such as mitophagy. Furthermore, we also review the recently identified FOXO-dependent retrograde signaling from stressed mitochondria to the nucleus, which suggest that FOXO mediates the crosstalk between these two important organelles to maintain cell homeostasis. In addition, we introduce a mitohormetic role of gamitrinib-triphenylphosphonium (G-TPP), a mitochondrial heat shock protein (Hsp) inhibitor that can induce mild mitochondrial stress to protect cells from future insults in a FOXO-dependent manner.