Integrative Machine Learning and Experimental Validation Identify FIS1 as a Candidate Biomarker Linked to...

Area of Science:

• Mitochondrial biology
• Cardiovascular research
• Molecular pathology

Background:

• Pulmonary hypertension (PH) involves complex pulmonary vascular remodeling with limited treatments.
• Mitochondrial dynamics are implicated in PH pathogenesis, but key regulators are undefined.

Purpose of the Study:

• To identify and functionally characterize genes regulating mitochondrial dynamics in PH.
• To explore the role of identified genes in pulmonary artery smooth muscle cell (PASMC) dysfunction and PH.

Main Methods:

• Integrated transcriptomic data with mitochondrial annotations.
• Prioritized candidate genes using WGCNA and machine learning.
• Validated findings in hypoxia-induced PH mouse models and cultured mouse PASMCs (mPASMCs) using molecular and cellular assays.

Main Results:

• Identified FIS1 as a key gene associated with PH, showing high discriminatory performance.
• Hypoxia increased FIS1 expression, leading to mitochondrial fragmentation, membrane potential loss, and ROS accumulation in mPASMCs.
• FIS1 knockdown suppressed mPASMC proliferation and migration, reduced mitochondrial injury, and attenuated ferroptosis.

Conclusions:

• FIS1 contributes to PH pathogenesis via mitochondrial fission and ferroptosis, promoting aberrant PASMC phenotypes and vascular remodeling.
• This study offers mechanistic insights and potential therapeutic targets within mitochondrial pathways for PH.