# Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Pulmonary hypertension (PH) is a progressive disorder associated with a variety of diseases commonly
afflicting veteran patients. Emerging evidence demonstrates that PH and excessive proliferation of pulmonary
artery smooth muscle cells (PASMC) are caused by derangements in mitochondrial function that impair
mitochondrial respiration and alter mitochondrial metabolic programming in a manner that enhances glycolytic
metabolism and diminishes oxidative phosphorylation. However, abnormalities in mitochondrial quality control
mechanisms that regulate mitophagy have not been investigated as a source of mitochondrial dysfunction and
PASMC hyperproliferation in PH, and will be explored in detail in the proposed studies.
 The proposed studies will investigate the role of the mitophagy initiator protein, PTEN-induced putative
kinase-1 (PINK1) in the pathogenesis of PH and PASMC proliferation. Our preliminary data demonstrate that
PINK1 is reduced in hypoxia-exposed PASMC in vitro and in the lungs and pulmonary artery tissues of rodents
that develop PH in hypoxic conditions. In the proposed studies, we will investigate the hypothesis that loss of
PINK1 causes impairments in mitophagy and mitochondrial metabolic programming that lead to
excessive PASMC proliferation in PH. Additional studies will define the mechanisms that regulate PINK1
loss in hypoxic conditions. We will test our hypothesis through the execution of the following Specific Aims:
 Aim 1 will investigate transcriptional and posttranscriptional mechanisms that regulate PINK1 through
microRNA (miR). Among several miRs identified by in silico analysis, miR-27a and miR-516a exhibited the
greatest differential expression changes in the hypoxic rodent lung and in hypoxic PASMC. Therefore, initial
studies will determine if PINK1 loss occurs through miR-27a- or miR-516a-mediated posttranscriptional
suppression of PINK1. To identify factors that regulate PINK1 transcription, we employed bioinformatics tools
to define predicted transcription factor (TF) binding sites in the PINK1 promoter. Among several TFs identified,
regulatory interactions between cAMP response element-binding protein (CREB) and PINK1 had not been
previously validated. Therefore, we will conduct studies using a PINK1 promoter luciferase reporter vector to
determine whether putative CREB binding sites are functional. To enhance the translational impact, we will
determine mechanisms that regulate PINK1 expression and activity using idiopathic pulmonary artery
hypertension (IPAH) PASMC and lung tissue.
 Aim 2 will characterize the functional consequences of PINK1 alterations on mitochondrial metabolic
reprogramming, mitophagy, and PASMC proliferation in PH. In isolated rat PASMC, the impact of hypoxia or
PINK1 gain and loss of function on mitochondrial oxygen consumption and glycolysis will be analyzed using
the Seahorse XF96 Bioanalyzer™. Additional studies will determine the effects of hypoxia or PINK1 alterations
on mitophagy in the...

## Key facts

- **NIH application ID:** 10476348
- **Project number:** 5I01BX004263-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** C MICHAEL HART
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476348

## Citation

> US National Institutes of Health, RePORTER application 10476348, Mitophagy in pulmonary hypertension: Novel roles of PTEN-Induced Kinase-1 in the pathobiology of pulmonary artery smooth muscle cell proliferation and mitochondrial dysfunction (5I01BX004263-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10476348. Licensed CC0.

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