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. 2016 Oct 25;6(10):e927.
doi: 10.1038/tp.2016.189.

Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines

R E Frye  1   2 , S Rose  1   2 , J Chacko  1 , R Wynne  1   2 , S C Bennuri  1   2 , J C Slattery  1   2 , M Tippett  1   2 , L Delhey  1   2 , S Melnyk  1   2 , S G Kahler  1   2 , D F MacFabe  3
Affiliations

Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines

R E Frye et al. Transl Psychiatry. .

Abstract

Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation product of the enteric microbiome. PPA is a normal intermediate of metabolism and is found in foods, either naturally or as a preservative. PPA and its derivatives have been implicated in both health and disease. Whereas PPA is an energy substrate and has many proposed beneficial effects, it is also associated with human disorders involving mitochondrial dysfunction, including propionic acidemia and autism spectrum disorders (ASDs). We aimed to investigate the dichotomy between the health and disease effects of PPA by measuring mitochondrial function in ASD and age- and gender-matched control lymphoblastoid cell lines (LCLs) following incubation with PPA at several concentrations and durations both with and without an in vitro increase in reactive oxygen species (ROS). Mitochondrial function was optimally increased at particular exposure durations and concentrations of PPA with ASD LCLs, demonstrating a greater enhancement. In contrast, increasing ROS negated the positive PPA effect with the ASD LCLs, showing a greater detriment. These data demonstrate that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD. As PPA, as well as enteric bacteria, which produce PPA, have been implicated in a wide variety of diseases, including ASD, diabetes, obesity and inflammatory diseases, insight into this metabolic modulator from the host microbiome may have wide applications for both health and disease.

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Figures

Figure 1
Figure 1
The potential effects of propionic acid on the citric acid cycle. (a) The citric acid cycle and associated electron transport chain complexes. The citric acid cycle is represented in the yellow circle with the enzymes of the cycle in blue ovals and the metabolites in black. The electron carriers derived from the citric acid cycle are represented in green ovals. These carriers are used by complex I and complex II of the electron transport chain (upper right corner) to produce energy. Complex V uses the energy produced by the electron transport chain to produce adenosine triphosphate (ATP), the energy carrier of the cell. (b) Predicted changes in citric acid cycle metabolism in the context of high propionic acid levels. Propionic acid uses a pathway that consumes acetyl-CoA to produce succinyl-CoA, an intermediate of the citric acid cycle. Thus, in the context of propionic acid, the first steps in the citric acid cycle may be bypassed and the production of nicotinamide adenine dinucleotide (NADH) may decrease. (c) 3-Nitropropionic acid (3NP), which could be generated from reactive nitrogen species interacting with propionic acid, inhibits succinic dehydrogenase, an important enzyme that produces a key energy carrier. This will not only decrease the production of flavin adenine dinucleotide (FADH2) but also the steps following, including malate dehydrogenase, another step that produces an electron carrier, NADH. This figure was adapted from Figures 1 and 2 in Frye et al.
Figure 2
Figure 2
Propionic acid (PPA) increases mitochondrial function in a concentration-dependent manner. Control lymphoblastoid cell lines were incubated for either 24 or 48 in PPA and mitochondrial function was measured. Average changes in mitochondrial function across the two incubation times is shown in the top row (a–d), whereas the difference in mitochondrial function between the two incubation times is shown in the bottom row of graphs (e–h). ATP-linked respiration (a) as well as maximal respiratory capacity (c) and reserve capacity (d) were elevated at 0.1 mM PPA relative to no PPA exposure with this effect greater with 24 h exposure as compared with 48 h exposure (e, g, h). Statistical significance levels: *P⩽0.05, **P⩽0.01, ***P⩽0.001, ****P⩽0.0001.
Figure 3
Figure 3
Oxidative stress reduces mitochondrial function and attenuates the effect of 24 h (a–d) and 48 h (e–h) propionic acid (PPA) incubation. Control lymphoblastoid cell lines were pretreated with 10 μM of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) for 1 h to increase intracellular reactive oxygen species before the mitochondrial assay after PPA had been washed from the cell culture. Overall DMNQ pretreatment increased proton leak respiration (c, g) and reduced maximal respiratory capacity (d, h) and reserve capacity (e, g). In addition, DMNQ pretreatment eliminated the positive effect of propionic acid on mitochondrial function seen without DMNQ pretreatment. The bars adjacent to the data lines represent the overall significant difference. Statistical significance levels: *P⩽0.05, **P⩽0.01, ***P⩽0.001, ****P⩽0.0001.
Figure 4
Figure 4
Propionic acid (PPA) enhances mitochondrial function in autistic lymphoblastoid cell lines (LCLs) over and above the effect it has on control LCLs in a concentration and exposure time-dependent manner. ATP-linked respiration, maximal respiratory capacity and reserve capacity were enhanced over and above control values at 0.1 mM for the autistic disorder with normal mitochondrial function (AD-N) LCLs with 24 h PPA incubation (a, c, d), whereas all of these mitochondrial parameters were enhanced at 0.1 and 1 mM for the autistic disorder with abnormal mitochondrial function (AD-A) LCLs with 48-h PPA incubation (e, g, h). Proton leak respiration was also significantly increased above control values for the autistic LCLs as compared with controls (b, f). The bars adjacent to the data lines represent overall significant differences. The color of the stars and bars represents the specific comparisons. Green represents the difference between AD-A and Control LCLs. Orange represents the difference between AD-N and Control LCLs. Blue represents the difference between the AD-N and AD-A LCLs. Statistical significance levels: *P⩽0.05, **P⩽0.01, ***P⩽0.001, ****P⩽0.0001.
Figure 5
Figure 5
Oxidative stress reduces mitochondrial function and reverses the enhancement effect of propionic acid (PPA) on mitochondrial function in autistic lymphoblastoid cell lines (LCLs). LCLs were pretreated with 10 μM of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) for 1h to increase intracellular reactive oxygen species before the mitochondrial assay after PPA had been washed from the cell culture. Although PPA increased ATP-linked respiration (a, e) and maximal respiratory capacity (c, g) above control values in a manner similar to the increase seen without DMNQ exposure, the increase in proton leak respiration was relatively greater (b, f), resulting in a net depletion in reserve capacity as compared with control LCLs (d, h). This is particularly true for the autistic disorder with abnormal mitochondrial function (AD-A) LCLs with a 48-h PPA incubation where the PPA concentrations that previously caused enhancement now result in a depletion in reserve capacity (h). The color of the stars and bars represents the specific comparisons. Green represents the difference between AD-A and control LCLs. Orange represents the difference between autistic disorder with normal mitochondrial function (AD-N) and control LCLs. Blue represents the difference between the AD-N and AD-A LCLs. Statistical significance levels: *P⩽0.05, **P⩽0.01, ***P⩽0.001, ****P⩽0.0001.
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