Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells.

Jae-Eun Song,Sungho Jin,Sabrina Diano,Matija Šestan-Peša,Tamas L. Horvath,Bernardo Stutz,Nicole Kilian,Richard G. Kibbey,Tiago C. Alves

doi:10.3390/metabo11050322

Abstract

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa cells. We observed the association between mitochondrial morphology and lipid droplet accumulation in response to high exogenous fatty acids. We inhibited mitochondrial fission by silencing dynamin-related protein 1(DRP1) and observed the shift in fatty acid storage-usage balance. Inhibition of mitochondrial fission resulted in an increase in fatty acid content of lipid droplets and a decrease in mitochondrial fatty acid oxidation. Next, we overexpressed carnitine palmitoyltransferase-1 (CPT1), a key mitochondrial protein in fatty acid oxidation, to further examine the relationship between mitochondrial fatty acid usage and mitochondrial morphology. Mitochondrial fission plays a role in distributing exogenous fatty acids. CPT1A controlled the respiratory rate of mitochondrial fatty acid oxidation but did not cause a shift in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning.

Highlights

Mitochondrial dynamics, fusion and fission of mitochondria, control mitochondrial morphology, which can reflect on different cell types [1,2], cell cycle [3] and nutrient and toxic stress the cell might be facing [4,5,6]
Cells incubated in base medium (BM) + palmitic acid (PA) had more, smaller mitochondria with more circular/shorter morphology, suggesting higher mitochondrial fragmentation or fission while BM + oleic acid (OA) caused no change in any Metabolites 2021, 11, 322 mitochondria parameters compared to mitochondria in cells incubated with no exogenous fatty acid (Figure S1A–D)
Cells incubated in BM + OA contained elongated mitochondria with increased accumulation of lipid droplets, whereas cells incubated in BM + PA contained smaller, less elongated mitochondria indicative of fission or fragmentation and no change in the amount of lipid droplets (Figure 1C,D)

Summary

Introduction

Mitochondrial dynamics, fusion and fission of mitochondria, control mitochondrial morphology, which can reflect on different cell types [1,2], cell cycle [3] and nutrient and toxic stress the cell might be facing [4,5,6]. The main emphasis of mitochondrial dynamics has been on the quality control of the mitochondrial population, which is heavily interconnected with cellular bioenergetics such as starvation or nutrient excess, because mitochondria are central organelles of metabolism [4,7]. The mechanistic connection between mitochondrial fission and lipid metabolism was first suggested via adenosine monophosphate (AMP)activated protein kinase (AMPK), a major enzyme in metabolic homeostasis. Mitochondrial fission factor (MFF) was identified as a substrate for AMPK, showing AMPK can directly regulate mitochondrial fission by mediating the recruitment of dynamin-related protein 1 (DRP1) to the mitochondrial outer membrane through MFF activation, proposing a link between mitochondrial fission and lipid metabolism [13]

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Conclusion