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

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.

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Mitochondrial fission governed by Drp1 regulates exogenous fatty acid usage and storage

10.1101/2020.10.17.343616 ◽

2020 ◽

Author(s):

Jae Eun Song ◽

Tiago C. Alves ◽

Bernardo Stutz ◽

Matija Sestan-Pesa ◽

Nicole Kilian ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Lipid Droplets ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Fatty Acid Content ◽

Acid Oxidation ◽

Exogenous Fatty Acid ◽

And Storage

ABSTRACTThe bioenergetic function of mitochondrial fission is associated with uncoupled respiration or elimination of damaged mitochondria to maintain a healthy mitochondrial population. In the presence of a high abundance of exogenous fatty acids, cells can either store fatty acids in lipid droplets or oxidize them in mitochondria. Even though carnitine palmitoyltransferase-1 (CPT1) controls the respiratory capacity of mitochondria in fatty acid oxidation, we observed that it did not dictate the balance of storage and usage of lipids in HeLa cells. On the other hand, inhibition of mitochondrial fission by silencing dynamic-related protein 1 (DRP1) resulted in an increase in fatty acid content of lipid droplets and a decrease in fatty acid oxidation. Mitochondrial fission was not only reflective of the amount of exogenous fatty acid being processed by mitochondria, but also found to be actively involved 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.

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Nrf2 affects the efficiency of mitochondrial fatty acid oxidation

Biochemical Journal ◽

10.1042/bj20130863 ◽

2014 ◽

Vol 457 (3) ◽

pp. 415-424 ◽

Cited By ~ 116

Author(s):

Marthe H. R. Ludtmann ◽

Plamena R. Angelova ◽

Ying Zhang ◽

Andrey Y. Abramov ◽

Albena T. Dinkova-Kostova

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Saturated Fatty Acids ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Atp Production ◽

Mitochondrial Fatty Acid ◽

Mitochondrial Oxidation ◽

Long Chain

Transcription factor Nrf2 affects fatty acid oxidation; the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) saturated fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively activated, affecting ATP production and FADH2 utilization.

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Estimation of peroxisomal and mitochondrial fatty acid oxidation in rat hepatocytes using tritiated substrates

Biochemical Journal ◽

10.1042/bj2790147 ◽

1991 ◽

Vol 279 (1) ◽

pp. 147-150 ◽

Cited By ~ 14

Author(s):

R Rognstad

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Specific Inhibitor ◽

Rat Hepatocytes ◽

Acid Oxidation ◽

Relative Distribution ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

The pathways of peroxisomal and mitochondrial fatty acid oxidation were monitored with the use of substrates which produce NAD3H. I used as marker substrates: D-[3-3H]3-hydroxybutyrate for mitochondrial NAD3H production, [2-3H]glycerol for cytosolic NAD3H production, and [2-3H]acetate to measure carbon-bound 3H which was also generated by the metabolism of the commercial 9,10-3H-labelled fatty acids. The assumption that peroxisomal NAD3H can be considered to be equivalent to cytosolic NAD3H was supported using a specific inhibitor of mitochondrial fatty acid oxidation. The approach involves determination of the specific yields, and the relative distribution on carbons 4 and 6, of 3H in glucose from the marker substrates and the labelled fatty acids. In hepatocytes from clofibrate-treated rats, the amount of palmitate or oleate oxidation which starts in the peroxisomes is comparable with that which starts in the mitochondria.

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3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90642.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. E497-E502 ◽

Cited By ~ 57

Author(s):

A. Lombardi ◽

P. de Lange ◽

E. Silvestri ◽

R. A. Busiello ◽

A. Lanni ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Atp Synthesis ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Amp Activated Protein Kinase

Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-l-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1 h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+104%), palmitoylcarnitine (+80%), or succinate (+30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to 1) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis (“proton leak”), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders.

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Plasma free fatty acids in mitochondrial fatty acid oxidation defects

Clinica Chimica Acta ◽

10.1016/s0009-8981(97)00130-7 ◽

1997 ◽

Vol 267 (2) ◽

pp. 143-154 ◽

Cited By ~ 20

Author(s):

G Martı́nez ◽

G Jiménez-Sánchez ◽

P Divry ◽

C Vianey-Saban ◽

E Riudor ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Free Fatty Acids ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Plasma Free Fatty Acids ◽

Mitochondrial Fatty Acid

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Lack of adrenal TSPO/PBR expression in hamsters reinforces correlation to triglyceride metabolism

Journal of Endocrinology ◽

10.1530/joe-20-0189 ◽

2020 ◽

Vol 247 (1) ◽

pp. 1-10

Author(s):

Prasanthi P Koganti ◽

Vimal Selvaraj

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Lipid Droplets ◽

Model Systems ◽

Translocator Protein ◽

Acid Oxidation ◽

Strong Positive Correlation ◽

Mitochondrial Fatty Acid Oxidation ◽

Triglyceride Metabolism ◽

Mitochondrial Fatty Acid

Despite being a highly conserved protein, the precise role of the mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), remains elusive. The void created by studies that overturned a presumptive model that described TSPO/PBR as a mitochondrial cholesterol transporter for steroidogenesis has been filled with evidence that it can affect mitochondrial metabolic functions across different model systems. We previously reported that TSPO/PBR deficient steroidogenic cells upregulate mitochondrial fatty acid oxidation and presented a strong positive correlation between TSPO/PBR expression and tissues active in triglyceride metabolism or lipid storage. Nevertheless, the highlighting of inconsistencies in prior work has provoked reprisals that threaten to stifle progress. One frequent factoid presented as being supportive of a cholesterol import function is that there are no steroid-synthesizing cell types without high TSPO/PBR expression. In this study, we examine the hamster adrenal gland that is devoid of lipid droplets in the cortex and largely relies on de novo cholesterol biosynthesis and uptake for steroidogenesis. We find that Tspo expression in the hamster adrenal is imperceptible compared to the mouse. This observation is consistent with a substantially low expression of Cpt1a in the hamster adrenal, indicating minimal mitochondrial fatty acid oxidation capacity compared to the mouse. These findings provide further reinforcement that the much sought-after mechanism of TSPO/PBR function remains correlated with the extent of cellular triglyceride metabolism. Thus, TSPO/PBR could have a homeostatic function relevant only to steroidogenic systems that manage triglycerides associated with lipid droplets.

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