Cardiolipin, Mitochondria, and Neurological Disease

Abstract

Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target. Lipids and the Central Nervous SystemThe central nervous system (CNS) is rich in lipids, which account for approximately 50% of the total brain dry weight [1]. They are primarily localized to biological membranes, where they sustain CNS architecture and function. Sphingolipids, glycerophospholipids, and cholesterol are the predominant species and participate in a broad range of physiological functions, including cellular signaling (e.g., myelination to enable neuronal communication and nerve conduction, and lipid raft formation), energy balance, blood-brain barrier formation, and inflammatory responses [2]. It is therefore unsurprising that dysregulation of the CNS lipidome is associated with a broad spectrum of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) [2].Neuronal cellular functions have an extremely high metabolic rate, with the brain consuming up to 20% of the total body energy [2]. To fulfil this extensive energy requirement, neurons rely on glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS). Indeed, mitochondria function as sophisticated energy sensors that rapidly modulate their morphology and activity according to cellular energy demands. In addition to energy metabolism, mitochondria also participate in numerous biochemical and signaling pathways that are crucial for brain homeostasis, including cell death signaling, generation of free radical species, and lipid synthesis [3]. As a consequence of their bacterial ancestry, mitochondria have distinctive features that include multiple copies of a circular geno...

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

“…In line with previous literature and to evaluate our cell culture system, we found a decreased total cardiolipin level [59][60][61]. Cardiolipin is beside PC and PE a major lipid and accounts for 10-15% of mitochondrial lipid content, being primarily localized in the inner membrane of mitochondria [73,77].…”

“…Several lines of evidence indicate that cardiolipin is strongly associated with neurological disorders, in particular, with AD [59]. Therefore, we would like to point out that the following results are not completely new investigations, but are important to evaluate whether our cell culture system results in similar cardiolipin changes found in other AD model systems or patients.…”

“…Cardiolipin is beside PC and PE a major lipid and accounts for 10-15% of mitochondrial lipid content, being primarily localized in the inner membrane of mitochondria [73,77]. Several roles of cardiolipin have been reported in particular in membrane architecture, mitophagy, mitochondrial dynamics, bioenergetics and protein import (e.g., reviewed in [59]). Therefore, cardiolipin has an indisputable role in mitochondrial function and energy homeostasis.…”

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“…The conversion of the phase-separated presynaptic neuronal protein α-syn from a physiological liquid-like droplet state into the pathological amyloid hydrogel aggregated state may also be facilitated by binding with externalized CL at OMM, ultimately disrupting mitochondrial membrane integrity and enhancing neurotoxicity [ 278 , 279 , 280 ]. Neurodegenerative disorders such as AD and PD have been associated with aberrant CL content, structure, and localization [ 281 ].…”

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