Mitochondrial dysfunction in benign prostatic hyperplasia

Don DeFranco, PhD

Sun, Youle, Finkel (2016). Mol. Cell

• α-adrenergic blockers treat the symptoms of BPH/LUTS

• 5α-reductase (5AR) inhibitors decrease prostate size• TURP may need to be performed if drug treatments

fail• Increased Cox-2 expression in inflammatory vs non-

inflammatory BPH • Combination therapies: 5ARi + NSAIDs (mixed results,

beneficial effects not long lasting) – Why?

Focal areas of Cox-2 overexpression in BPH (DamberLab, 2004)

TREATMENT FOR BPH/LUTS

Reciprocal Regulation of Cox-1 and Cox-2BPH-1 Cells

+ 12-HHT

COX-1 vs COX-2 in MF:Differential gene expression(Li X et al., (2018) J. Lipid Res.)

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Cox-2

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Cox-1Cox-2

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COX-1 IHC in Human Prostate

Statistically significant increase in COX-1 expression in BPH compared to normal adjacent tissue.

Physiologic or Pathophysiologic Regulators of COX-1?

Age-dependent gradual mitochondrial dysfunction:Is this relevant to BPH progression?

Sun, Youle, Finkel (2016). Mol. Cell

FibrosisT. Liu T. Liu

Epi Barrier

Focus on ETC Complex I: Dysfunction associated with human diseases

Rotenone: an inhibitor of complex I of the mitochondrial respiratory chain

q Leading to a blockade of oxidative phosphorylation with limited ATP production;

q Incomplete electron transfer to oxygen could cause the formation of ROS.

Rotenone exposure has been shown to correlate with the occurrence of several Parkinson’s disease (PD)-like symptoms in humans. Chronic administration of rotenone has been used to create experimental animal models of PD.

NDUFS3

Project 3: ROTENONE: MODEL MITOCHONDRIAL ETC COMPLEX I DYSFUNCTION

Age-dependent decline in NDUFS3 in human prostate (T. Liu, UWisconsin)

Hypothesis: Age-dependent decline in mitochondrial ETC Complex I activity contributes to BPH pathogenesis

Repression of NDUFS3 in prostates of rotenone-treated rats

T. Liu, W. Ricke (UW),R DiMaio, JT Greenamyre (Pitt)

Rotenone induction of COX-1 & COX-2 in RWPE-1 Cells (K. He)

TOM 20 IIF (D. Stolz) in BPH tissueCompensatory increase in mito mass?

Normal BPHNDUFS3- ETC Complex I protein

ROTENONE DISRUPTS AUTOPHAGIC FLUX (MITOPHAGY?) IN PrECs

RotE F

MITOPHAGY ASSESSMENTProximity Ligation AssayTom20 & p62 ColocalizationRWPE-1 Cells(K. He & R. Di Maio)

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e

Rot 10n

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Rot 25n

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Rot 50n

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Diversion of p62 to damage mito?

Rotenone Effects on Cell Junction ProteinsIn RWPE-1 Cells Kai He

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In Vivo Rat Study (Neuroniol Dis 2018): Rotenone treatment induced intestinal hyperpermeability and disrupted expression of ZO-1, Occludin, Claudin-1)

C D K N 1 A (p 2 1 ) P P AR G C 1 A C O L 1 A1 C O L 3 A1 AC T A2 T G F b0

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p21 PPARGC1A Col1a1 Col3a1 ACTA2 TGFβsenescence mitochondrial

functionfibrosis

Rela

tive

mRN

A Ex

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sion

Does mitochondrial dysfunction contribute to prostatic fibrosis?

Zank DC et al., (2018) Front. Med.Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics

BhPrS1 Cells (T. Liu, W. Ricke)Lessons from idiopathic pulmonary fibrosis

FUTURE DIRECTIONSIs mitochondrial (ETC Complex I) dysfunction (or altered mitophagy) associated with the BPH progression?

Complex-I Alteration and Enhanced Mitochondrial Fusion Are Associated With Prostate Cancer Progression.Philley JV, et al., J Cell Physiol. 2016 Jun;231(6):1364-74. PMID: 26530043

“Respiratory Complex I-mtDNA mutations (in the NADH ubiquinone oxidoreductase chain 4 gene), MFN2, and IMMT proteins were detected in the circulating exosomes in serum of men with benign prostate hyperplasia (BPH) and progressive PCa!

NDUFS3

Succinate

Can drugs that “restore” mitochondrial function reverse various phenotypes observed with in vitro and in vivo models of prostatic epithelial cell dysfunction, inflammation, or LUTS?

AcknowledgmentsUniv of Pittsburgh

O’Brien CenterDeFranco LabKai HeChandler HudsonCaroline Madigan

Zhou WangLaura PascalNaoki YoshimuraRajiv DhirPooja Srivastava

Pittsburgh Institute for Neurodegenerative Diseases

Tim GreenamyreRoberto Di Maio

Mel

NIDDK: U54 DK112079

Univ. Wisconsin O’Brien CenterWill Ricke - PIEmily RickeTeresa Liu – K12 ScholarLiv Myklebust – CAIRIBU Research Training and Development Awardee

Kai

Laura

Zhou

Caroline

Teresa Liv

Will

RobertoTim