Mitochondrial Translocase TOMM22 Is Overexpressed in Pancreatic Cancer and Promotes Aggressive Growth by Modulating Mitochondrial Protein Import and Function

Author:

Haastrup Mary Oluwadamilola12ORCID,Vikramdeo Kunwar Somesh12ORCID,Anand Shashi12ORCID,Khan Mohammad Aslam12ORCID,Carter James Elliot2ORCID,Singh Seema123ORCID,Singh Ajay Pratap123ORCID,Dasgupta Santanu123ORCID

Affiliation:

1. 1Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.

2. 2Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.

3. 3Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama.

Abstract

Abstract Pancreatic cancer has the worst prognosis among all cancers, underscoring the need for improved management strategies. Dysregulated mitochondrial function is a common feature in several malignancies, including pancreatic cancer. Although mitochondria have their own genome, most mitochondrial proteins are nuclear-encoded and imported by a multi-subunit translocase of the outer mitochondrial membrane (TOMM). TOMM22 is the central receptor of the TOMM complex and plays a role in complex assembly. Pathobiologic roles of TOMM subunits remain largely unexplored. Here we report that TOMM22 protein/mRNA is overexpressed in pancreatic cancer and inversely correlated with disease outcomes. TOMM22 silencing decreased, while its forced overexpression promoted the growth and malignant potential of the pancreatic cancer cells. Increased import of several mitochondrial proteins, including those associated with mitochondrial respiration, was observed upon TOMM22 overexpression which was associated with increased RCI activity, NAD+/NADH ratio, oxygen consumption rate, membrane potential, and ATP production. Inhibition of RCI activity decreased ATP levels and suppressed pancreatic cancer cell growth and malignant behavior confirming that increased TOMM22 expression mediated the phenotypic changes via its modulation of mitochondrial protein import and functions. Altogether, these results suggest that TOMM22 overexpression plays a significant role in pancreatic cancer pathobiology by altering mitochondrial protein import and functions. Implications: TOMM22 bears potential for early diagnostic/prognostic biomarker development and therapeutic targeting for better management of patients with pancreatic cancer.

Funder

National Cancer Institute

U.S. Department of Defense

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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