High-fat diet effects on brain mitochondrial complex I activity and protein lipoxidation: implications for translational medicine

Abstract

Recent research has highlighted the significant effects of high-fat diets (HFDs) on brain health, particularly focusing on mitochondrial complex I activity and protein lipoxidation. Mitochondrial complex I, the first enzyme of the electron transport chain, is crucial for oxidative phosphorylation and adenosine triphosphate (ATP) production. In individuals consuming an HFD, complex I activity notably increases, initially appearing beneficial due to enhanced energy production. However, this upregulation is linked to elevated reactive oxygen species (ROS) production, leading to oxidative stress and mitochondrial dysfunction. Over the past 5 years, studies have associated this imbalance with neurodegenerative conditions and cognitive decline in obese individuals.¹

The brain's energy demands are met primarily through oxidative phosphorylation, with mitochondrial complex I playing a pivotal role. In the context of an HFD, complex I activity is upregulated, ostensibly to meet increased energy requirements. However, this heightened activity has a significant downside. Increased complex I activity is closely associated with ROS production, chemically reactive molecules containing oxygen. While ROS are normal byproducts of cellular metabolism, excessive ROS production can overwhelm the cell's antioxidant defences, leading to oxidative stress (Figure 1).^{2, 3}

Oxidative stress is a critical factor in the pathogenesis of neurodegenerative diseases. It damages cellular components, including lipids, proteins and DNA, disrupting normal cellular functions and leading to cell death. In the brain, which has a high metabolic rate and limited regenerative capacity, oxidative stress is particularly detrimental. Studies have shown that in obese individuals, the brain exhibits higher levels of oxidative damage, correlated with cognitive impairments and increased risk of neurodegenerative disorders such as Alzheimer's disease. Lipoxidation, the oxidative modification of proteins by lipid peroxidation products, is another significant consequence of a HFD. Lipid peroxidation is a process where ROS attack polyunsaturated fatty acids in cell membranes, resulting in the formation of reactive lipid aldehydes. These aldehydes can covalently modify proteins, forming advanced lipoxidation end-products (ALEs). ALEs accumulate in neural tissues and alter protein structure and function, leading to impaired cellular processes and neuronal damage.^{4, 5}

The brain's synaptic function is particularly vulnerable to lipoxidation. Synaptic proteins are essential for neurotransmission, and their modification by ALEs can disrupt signal transduction, leading to synaptic dysfunction, cognitive deficits and neurodegenerative changes. Recent studies have provided evidence that the increased ROS production due to elevated complex I activity accelerates lipid peroxidation, thereby enhancing protein lipoxidation. The resultant protein damage exacerbates neuroinflammation and promotes the progression of neurodegenerative diseases. The relationship between dietary fats and neural health is complex and multifaceted, involving both mitochondrial and proteomic changes. HFDs have been shown to alter mitochondrial dynamics, including biogenesis, fusion and fission, which are critical for maintaining mitochondrial function and neuronal health. Mitochondrial biogenesis is the process by which new mitochondria are formed, while fusion and fission regulate mitochondrial morphology and function. Disruptions in these processes can lead to mitochondrial dysfunction, contributing to cellular stress and neuronal damage.⁶

Proteomic analyses have revealed that HFDs lead to differential expression of proteins involved in energy metabolism, antioxidant defences and inflammatory responses in the brain. These proteomic changes indicate the brain's attempt to adapt to the metabolic stress imposed by an HFD. However, these adaptations are often insufficient to counteract the detrimental effects of increased ROS production and lipoxidation. The altered expression of proteins involved in energy metabolism suggests a shift in cellular energy production pathways, potentially leading to energy deficits in neurons.⁷ Similarly, changes in antioxidant defence proteins reflect the brain's efforts to combat oxidative stress, though these defences are often overwhelmed by excessive ROS production. Understanding the effects of HFDs on brain health underscores the importance of dietary patterns in neurological well-being. This knowledge is crucial for clinical and translational medicine, as it informs the development of targeted interventions to mitigate the adverse effects of HFDs on the brain. Interventions could focus on modulating mitochondrial function and reducing protein lipoxidation to protect neural health in the context of dietary-induced obesity. By integrating dietary recommendations, lifestyle modifications and targeted therapies, clinicians can better support neurological well-being and prevent cognitive decline in the face of dietary challenges.⁸

Vetriselvan Subramaniyan and Ainil Hawa Jansi: Conceptualization; Methodology; Supervision; Writing review and editing. Harshini Muruganantham: Resources and final proofreading.

The authors declare no conflicts of interest.