FoxO transcription factors in mitochondrial homeostasis

Abstract

Mitochondria play essential roles in cellular energetics, biosynthesis, and signaling transduction. Dysfunctional mitochondria have been implicated in different diseases such as obesity, diabetes, cardiovascular disease, nonalcoholic fatty liver disease, neurodegenerative disease, and cancer. Mitochondrial homeostasis is controlled by a triad of mitochondrial biogenesis, dynamics (fusion and fission), and autophagy (mitophagy). Studies have underscored FoxO transcription factors as key mitochondrial regulators. Specifically, FoxOs regulate mitochondrial biogenesis by dampening NRF1-Tfam and c-Myc-Tfam cascades directly, and inhibiting NAD-Sirt1-Pgc1α cascade indirectly by inducing Hmox1 or repressing Fxn and Urod. In addition, FoxOs mediate mitochondrial fusion (via Mfn1 and Mfn2) and fission (via Drp1, Fis1, and MIEF2), during which FoxOs elicit regulatory mechanisms at transcriptional, posttranscriptional (e.g. via miR-484/Fis1), and posttranslational (e.g. via Bnip3-calcineurin mediated Drp1 dephosphorylation) levels. Furthermore, FoxOs control mitochondrial autophagy in the stages of autophagosome formation and maturation (e.g. initiation, nucleation, and elongation), mitochondria connected to and engulfed by autophagosome (e.g. via PINK1 and Bnip3 pathways), and autophagosome-lysosome fusion to form autolysosome for cargo degradation (e.g. via Tfeb and cathepsin proteins). This article provides an up-to-date view of FoxOs regulating mitochondrial homeostasis and discusses the potential of targeting FoxOs for therapeutics.

Hormonal regulation of metabolism—recent lessons learned from insulin and estrogen

“…Mitochondrion is an organelle that primes biochemical processes of respiration and energy production [ 55–57 ]. Its homeostasis is jointly maintained by mitochondrial biogenesis, mitochondrial dynamics (fusion or fission), and mitophagy (mitochondrial autophagy) [ 12 , 58 ]. Insulin signaling mediates mitochondrial function and disease status [ 56 , 57 ], which is fine-tuned through FoxOs and PGC1α ( Figure 1 B).…”

“…Insulin signaling mediates mitochondrial function and disease status [ 56 , 57 ], which is fine-tuned through FoxOs and PGC1α ( Figure 1 B). FoxOs play key roles in the triad of mitochondrial biogenesis, dynamics, and mitophagy as a transcription factor in the canonical IRS-PI3K-Akt insulin signaling pathway [ 12 ]. FoxOs differentially regulate mitochondrial biogenesis via Tfam, NRF1, and PGC1α in different tissues ( Figure 1 B) [ 12 , 59 , 60 ].…”

“…FoxOs play key roles in the triad of mitochondrial biogenesis, dynamics, and mitophagy as a transcription factor in the canonical IRS-PI3K-Akt insulin signaling pathway [ 12 ]. FoxOs differentially regulate mitochondrial biogenesis via Tfam, NRF1, and PGC1α in different tissues ( Figure 1 B) [ 12 , 59 , 60 ]. FoxOs affect mitochondrial dynamics mainly through transcriptionally up-regulate the fusion proteins Mfn1/2 and down-regulate fission protein Drp1 ( Figure 1 B) [ 12 , 61 ].…”

“…Studies have established canonical insulin signaling pathways (e.g., IRS-PI3K-PDK1-Akt) and non-canonical insulin signaling pathways (e.g., IRS-PI3K-PDPK1-aPKCλ) in the regulation of glucose metabolism [ 7 , 10 ]. Moreover, insulin signaling modulates mitochondrial metabolism including mitochondrial biogenesis, dynamics, and autophagy (mitophagy, a mitochondrial quality control system that allows for the elimination of damaged and redundant mitochondria) [ 11 ], primarily through the Forkhead box O (FoxO) transcription factors [ 12 ]. Recent research has revealed the epigenetic role of insulin signaling via Snail and Slug in metabolic disorders [ 13–15 ].…”

“…Accumulated evidence has linked estrogen signaling to insulin signaling in metabolic regulation. For instance, both insulin and estrogen signaling cascades are involved in the regulation of mitochondria, autophagy, and protein degradation [ 12 , 23–25 ]. Sirt1 and PI3K serve as the mediators in the crosstalk of insulin and estrogen signaling, which plays essential roles in metabolism [ 26–28 ].…”