Mitochondrial positioning supports localized energy and signaling requirements. Miro1 is necessary for attachment of mitochondria to microtubule motor proteins for trafficking. When Miro1 is deleted ( Show more
Mitochondrial positioning supports localized energy and signaling requirements. Miro1 is necessary for attachment of mitochondria to microtubule motor proteins for trafficking. When Miro1 is deleted (Miro1-/-) from mouse embryonic fibroblasts (MEFs), mitochondria become sequestered to the perinuclear space, disrupting subcellular signaling gradients. Here, we show that Miro1-/- MEFs grow slower than Miro1+/+ and Miro1-/- MEFs stably re-expressing a Myc-Miro1 plasmid. Miro1-/- MEFs have a decreased percentage of cells in G1 and increased percentage of cells in S phase. We conducted the first ever RNA sequencing experiment dependent upon Miro1 expression and found differentially expressed genes related to MAPK signaling, cell proliferation and migration. ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) phosphorylation is elevated both spatially and temporally following serum stimulation in Miro1-/- MEFs, whereas the expression levels and oxidation of the dual specificity phosphatases (DUSP1-DUSP6) is unchanged. Finally, we found the oxidation status of ERK1/2 is increased in Miro1-/- MEFs compared to that seen in Miro1+/+ and Myc-Miro1 MEFs. These results highlight transcriptional control based off Miro1 expression and demonstrate the dynamic regulation of ERK1/2 upon deletion of Miro1 which might support the observed cell cycle and proliferation defects. Show less
Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fruc Show more
Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. Hepatic expression of In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis. Show less