TABLE 2.
The potential effects of medium chain fatty acids (MCFAs) on autophagy and mitochondrial function in aging and neurodegenerative diseases.
| MCFA | Effects on autophagy and mitochondrial dysfunction in: | References | |||
| Aging | Alzheimer’s disease (AD) | Amyotrophic lateral sclerosis (ALS) | Parkinson’s disease (PD) | ||
| Hexanoic acid | No literature available | ||||
| Heptanoic acid | No literature available | ||||
| Octanoic acid | Stimulates JNK-dependent autophagy, known to extend the lifespan in Drosophila | – | – | – | Wang et al., 2005; He et al., 2022 |
| Nonanoic acid | – | – | – | – | |
| Decanoic acid | Increases autophagy by Atg1 and Atg8a upregulation. Reduced autophagy contributes to functional decline in aging. Reduces oxidative stress, increase mitochondria biogenesis, and upregulate mitochondrial respiratory chain enzymes via activation of PPARγ, SIRT1 and SIRT3. Elevated oxidative stress and reduced mitochondrial function contribute to functional decline in aging. |
Reduces excitotoxicity by AMPAR inhibition. Over-excitation of the AMPAR contributes to AD. | Decreases autophagy by inhibiting mTORC1 in patient-derived astrocytes. mTORC1 inhibition was previously shown to improve locomotion in zebrafish ALS model. Reduces excitotoxicity by AMPAR inhibition. Over-excitation of the AMPAR contributes to ALS. |
Reduces excitotoxicity by AMPAR inhibition. Over-excitation of the AMPAR contributes to PD. Reduces dopaminergic neuron loss and oxidative stress via activation of SIRT3. Reduced SIRT3 was reported with dopaminergic neuron loss and increased oxidative stress in the PD mouse model. |
Johnson et al., 2009; Van Damme, 2009; Malapaka et al., 2012; Hughes et al., 2014; Joshi et al., 2015; Lattante et al., 2015; Liu et al., 2015; Chang et al., 2016; Mesquita et al., 2017; Whitehead et al., 2017; Jurado, 2018; Dabke and Das, 2020; Warren et al., 2020, 2021; Akamatsu et al., 2022 |
| Undecanoic acid | No literature available | ||||
| Dodecanoic acid | – | – | – | Reduces augmented autophagy by decreasing Atg5 and Beclin-1. LRRK2 mutations increase autophagy, resulting in neurite shortening which precedes neuronal death. |
Plowey et al., 2008; Sekar et al., 2018 |
| Medium-chain triglyceride (MCT) ketogenic diet, consisting of various MCFAs | Nutritional ketosis upregulates autophagy by inhibiting mTORC1. Reduced autophagy contributes to functional decline in aging. Upregulates mitochondrial respiratory chain enzymes. Promotes autophagy and mitochondrial biogenesis via AMPK and PGC-1α activation. |
Ketone-dependent autophagy regulation of HMGS2, an enzyme controlling ketone synthesis from MCFAs, reduces amyloid-β plaques | Promotes mitochondrial ATP synthesis and prevents complex I inhibition. | Ketones generated from MCFA metabolism directly promote chaperone-mediated autophagy (CMA). Activation of CMA induces LRRK2 and α-synuclein degradation. Improves mitochondrial respiration by reducing glutamate- induced ROS. ROS production induced by excitotoxicity of glutaminergic neurones was observed in PD |
Cuervo and Dice, 2000; Finn and Dice, 2005; Zhao et al., 2006; Jäger et al., 2007; Maalouf et al., 2007; Egan et al., 2011; McDaniel et al., 2011; Orenstein et al., 2013; McCarty et al., 2015; Hu et al., 2017; Dabke and Das, 2020 |