Impaired lipid homeostasis and mitochondrial dysfunction in critical limb ischaemia caused by arteriosclerosis...

Area of Science:

• Biochemistry
• Molecular Biology
• Vascular Medicine

Background:

• Critical limb ischaemia (CLI) is a severe peripheral artery disease characterized by reduced blood flow.
• CLI disrupts lipid metabolism and mitochondrial function, leading to muscle atrophy, impaired repair, and increased risk of limb loss.
• Current diagnostics for CLI primarily rely on imaging and perfusion, often overlooking critical metabolic alterations.

Purpose of the Study:

• To investigate lipid alterations in CLI using a novel framework.
• To identify potential non-invasive biomarkers for early CLI detection and treatment.
• To explore the relationship between lipid changes, mitochondrial dysfunction, and CLI progression.

Main Methods:

• Development and application of the LIPID-CLI framework utilizing high-resolution mass spectrometry.
• Analysis of lipid profiles, focusing on ceramides and phospholipids, in patients with CLI.
• Shift from invasive tissue biopsies to analysis of blood markers that reflect tissue lipid composition.

Main Results:

• The LIPID-CLI method identified significant alterations in ceramides and phospholipids associated with mitochondrial stress in CLI.
• Specific lipid markers, including ceramides, phospholipid ratios, acylcarnitines, and oxidized phospholipids (OxPLs), showed quantifiable changes.
• A reduced ceramide concentration, normalized to total lipid content, was observed, indicating disrupted lipid homeostasis and mitochondrial dysfunction.

Conclusions:

• Altered lipid profiles, particularly ceramides and phospholipids, are indicative of lipid-mitochondrial dysfunction in CLI.
• These lipid alterations may serve as novel, non-invasive biomarkers for the early diagnosis and effective treatment of CLI.
• The LIPID-CLI framework offers a promising approach to understanding and managing the metabolic derangements in CLI.