Fasting the mitochondria to prevent neurodegeneration: the role of ceramides

Abstract

Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.

Keywords: ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration.

Figure 1

Ceramides modulate neuronal development, function, and protection. C18:0, C16:0 and C24:0 maintain plasma membrane integrity and fluidity. C20:0, C24:0 and ceramide-1-phosphate (C1P) are also involved in the fine regulation of processes including cell growth, differentiation, neuroplasticity and apoptosis. C24:0 ceramide supports myelination and axonal health, indirectly protecting neuronal endings and facilitating signal propagation to synaptic terminals. Ceramides, particularly C16:0, C18:0, and C24:0, play significant roles in modulating neurotransmitter release coordinating excitotoxicity and ensuring proper neuronal communication. Abbreviations: ceramide-1-phosphate (C1P).

Figure 2

Ceramide-driven mitochondrial regulation. Ceramides modulates mitochondria dynamics by several pathways. (1) Lipid membrane composition: C2:0 and C16:0 ceramides increase mitochondrial membrane permeability by integrating channels into the inner mitochondria membrane assisting cytochrome c release. (2) Disruption of electron transport chain: C2:0 and C16:0 ceramides or CerS2 overexpression promoted ROS production via mPTP interaction and Complex III inhibition (antimycin A site). Also, C16:0 inhibits Complex IV and CPT1, disrupting β-oxidation. (3) Ceramides activates apoptosis and mitophagy: C16:0 and C18:0 promoted Bcl-2 depletion and Akt inhibition and activated apoptosis by MOMP through Bcl-xL-sensitive channel formation and interaction with Bax/VDAC. C18:0 ceramide, produced by CerS1 transported via p17/PERMIT, triggers mitophagy through LC3B-II independently of caspases. ASM and ceramides coordinate mitophagosome formation. Conversely, CerS6 impairs mitophagy via SQSTM1 interaction. Ceramide synthase 2, CerS2; Ceramide synthase 6, CerS6.

Figure 3

Schematic representation of the negative effects of ceramide in mitochondria physiology and mitophagy and a possible beneficial effect of intermittent fasting on mitochondria. Ceramide overproduction produces negative effects on mitochondria physiology such as an alteration in the mitochondrial respiratory chain function and ROS accumulation leading to oxidative stress. Furthermore, increasing levels of ceramide, especially C18:0 specie activates mitophagy. Conversely, IF improves mitochondrial function in several cell types by reducing ceramide production, reducing the ROS production by increasing antioxidant enzyme levels, production of cardiolipin levels in the mitochondria membrane, and improving the electron transport chain by enhancing mitochondrial oxidative metabolism and mitochondrial respiratory control rate. IF also can induce mitophagy to remove damaged mitochondria by several cellular insults. Scheme created in https://BioRender.com.